Compositions and methods for the treatment of tauopathy

ABSTRACT

The disclosure provides compositions and methods for the preparation, manufacture and therapeutic use of viral vectors, such as adeno-associated virus (AAV) particles having viral genomes encoding one or more antibodies or antibody fragments or antibody-like polypeptides, for the prevention and/or treatment of diseases and/or disorders.

REFERENCE TO RELEVANT APPLICATIONS

This application claims the benefit of U.S. Provisional Patent Application No. 62/839,891, entitled “Compositions and Methods for the Treatment of Tauopathy”, filed Apr. 29, 2019 and U.S. Provisional Patent Application No. 63/002,011, entitled “Compositions and Methods for the Treatment of Tauopathy” filed Mar. 30, 2020; the contents of each of which are herein incorporated by reference in their entirety.

REFERENCE TO THE SEQUENCE LISTING

The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing file, entitled 20571304PCT.txt, was created on Apr. 29, 2020, and is 18,423,475 bytes in size. The information in electronic format of the Sequence Listing is incorporated herein by reference in its entirety.

FIELD OF THE DISCLOSURE

The disclosure relates to compositions and methods for vectored antibody delivery (VAD), wherein the antibody may be an anti-tau antibody.

BACKGROUND

Tauopathies are a group of neurodegenerative diseases characterized by the dysfunction and/or aggregation of the microtubule associated protein tau. Tau is normally a very soluble protein known to associate with microtubules based on the extent of its phosphorylation. Tau is considered a critical component of intracellular trafficking processes, particularly in neuronal cells, given their unique and extended structure. Hyperphosphorylation of tau depresses its binding to microtubules and microtubule assembly activity. Further, hyperphosphorylation of tau renders it prone to misfolding and aggregation. In tauopathies, the tau becomes hyperphosphorylated, misfolds and aggregates as neurofibrillary tangles (NFT) of paired helical filaments (PHF), twisted ribbons or straight filaments. These NFT are largely considered indicative of impending neuronal cell death and thought to contribute to widespread neuronal cell loss, leading to a variety of behavioral and cognitive deficits.

The first genetically defined tauopathy was described when mutations in the tau gene were shown to lead to an autosomal dominantly inherited tauopathy known as frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). This was the first causal evidence that changes in tau could lead to neurodegenerative changes in the brain. These molecules are considered to be more amyloidogenic, meaning they are more likely to become hyperphosphorylated and more likely to aggregate into NFT (Hutton, M. et al., 1998. Nature 393(6686):702-5).

Other known tauopathies include, but are not limited to, Alzheimer's disease (AD), Frontotemporal lobar degeneration (FTLD), Frontotemporal dementia, chronic traumatic encephalopathy (CTE), Progressive Supranuclear Palsy (PSP), Down's syndrome, Pick's disease, Corticobasal degeneration (CBD), Corticobasal syndrome, Amyotrophic lateral sclerosis (ALS), Prion diseases, Creutzfeldt-Jakob disease (CJD), Multiple system atrophy, Tangle-only dementia, and Progressive subcortical gliosis.

Several approaches have been proposed for therapeutically interfering with progression of tau pathology and preventing the subsequent molecular and cellular consequences. Given that NFT are composed of hyperphosphorylated, misfolded and aggregated forms of tau, interference at each of these stages has yielded a set of avidly pursued targets. Introducing agents that limit phosphorylation, block misfolding or prevent aggregation have all generated promising results. Passive and active immunization with late stage anti-phospho-tau antibodies in mouse models have led to dramatic decreases in tau aggregation and improvements in cognitive parameters. It has also been suggested that introduction of anti-tau antibodies can prevent the trans-neuronal spread of tau pathology.

Antibodies have relatively short half-lives, and this presents an ongoing and long-felt challenge for antibody-based therapies. In order to achieve a sufficiently high concentration of an antibody for long lasting therapeutic effects, antibody therapies are traditionally delivered by repeated administration, e.g. by multiple injections. This dosing regimen results in an inconsistent level of antibody throughout the treatment period, limited efficiency per administration, high cost of administration and consumption of the antibody. Hence, there remains a need in the art for delivery of antibodies and antibody-based therapeutics through alternative routes or modalities of administration.

One such alternative route of administration is by expression vectors (e.g. plasmid or viral vector), including but not limited to, adeno-associated viral vectors (AAVs). Adeno-associated viral vectors are widely used in gene therapy approaches due to a number of advantageous features. As dependoparvoviruses, AAV are non-replicating in infected cells and therefore not associated with any known disease. Further, AAVs may be introduced to a wide variety of host cells, do not integrate into the genome of the host cell, and are capable of infecting both quiescent and dividing cells. AAVs transduce non-replicating and long-lived cells in vivo, resulting in long term expression of the protein of interest. Further, AAVs can be manipulated with cellular and molecular biology techniques to produce non-toxic particles carrying a payload encoded in the AAV viral genome that can be delivered to a target tissue or set of cells with limited or no side-effects. Given the foregoing, the use of AAVs for vectored antibody delivery (VAD) of anti-tau antibodies would allow for longer lasting efficacy, fewer dose treatments, and more consistent levels of the antibody throughout the treatment period.

In vectored antibody delivery (VAD) of anti-tau antibodies, an AAV is used as the delivery modality for a nucleic acid sequence encoding the anti-tau antibody, or a fragment thereof, which results in in vivo expression of the encoded payload, e.g., functional anti-tau antibody, or a fragment thereof.

The mechanism underlying VAD is thought to proceed through the following steps. First, the AAV vector enters the cell via endocytosis, then escapes from the endosomal compartment and is transported to the nucleus wherein the viral genome is released and converted into a double-stranded episomal molecule of DNA by the host. The transcriptionally active episome results in the expression of encoded anti-tau antibodies that may then be secreted from the cell into the circulation. VAD may therefore enable continuous, sustained and long-term delivery of anti-tau antibodies administered by a single injection of AAV particles.

Previous studies of an AAV-mediated antibody technique known as vectored immunoprophylaxis (VIP) have focused on neutralization of human immunodeficiency virus (HIV) (see, e.g. Johnson et al., 2009, Nature Med., 15, 901-906, Saunders et al., 2015, J. Virol., 89(16), 8334-8345, Balasz et al., 2012, Nature 481, 81-84, the contents of which are incorporated herein by reference in their entirety). Balasz et al. reported a long-term, even lifelong, expression of monoclonal antibody at high concentration from a single intramuscular administration in mice that resulted in full protection against HIV infection. AAV-mediated VIP has also been demonstrated against influenza strains (see, e.g. Balasz, et al. Nat. Biotechnol., 2013, 31(7):647-52) and Plasmodium Falciparum, a sporozoite causing malaria infection (see, e.g. Deal at al., 2014, PNAS, 111 (34), 12528-12532), as well as cancer, RSV and drug addiction (see, e.g. review by Schnepp and Johnson, Microbiol. Spectrum 2(4), 2014). Though promising, these studies emphasize efforts to prevent disease. There still remains a need for improved methods of prevention, and new antibody-mediated therapies for research, diagnosis, and treatment of disease.

The present disclosure addresses this need by providing novel AAV particles having viral genomes engineered to encode anti-tau antibodies and antibody-based compositions and methods of using these constructs (e.g., VAD) for the treatment, prevention, diagnosis and research of diseases, disorders and/or conditions associated with tau pathology. The present disclosure further embraces optimized AAV particles for delivery of nucleic acids (e.g., viral genomes) encoding anti-tau antibodies and antibody-based compositions to a subject in need thereof.

SUMMARY

The present disclosure describes AAV particles for delivery of anti-tau antibodies to a target tissue. AAV particles of the present disclosure may comprise an AAV capsid and a viral genome.

Viral genomes of the present disclosure may comprise a 5′ ITR with a sequence selected from SEQ ID NO: 2076 or 2077, one or more promoter regions with a sequence selected from SEQ ID NO: 2080-2089 and 2238-2239, an antibody polynucleotide with a sequence selected from SEQ ID NO: 1740-1989, 2241-2243 and 2169-2170, or encoding a sequence selected from SEQ ID NO: 1740-1989, 2241-2243 and 2169-2170, a polyadenylation signal sequence with a sequence selected from SEQ ID NO: 2122-2124, and a Y ITR with a sequence selected from SEQ ID NO: 2078-2079. In some embodiments, viral genomes described herein may comprise one or more exon sequences with a sequence selected from SEQ ID NO: 2090-2094. In some embodiments, viral genomes described herein may comprise one or more intron sequences with a sequence selected from SEQ ID NO: 2095-2105, 2240 and 2256-2258. In some embodiments, viral genomes described herein may comprise one or signal sequence regions with a sequence selected from SEQ ID NO: 1740, 1741, 1861, 2106-2117 and 2241. In some embodiments, the signal sequence region is derived from an antibody sequence. In some embodiments, viral genomes described herein may comprise one or more tag sequence regions with a sequence selected from SEQ ID NO: 2118-2121 and 2255. In some embodiments, the viral genomes described herein may comprise a filler sequence region with a sequence selected from SEQ ID NO: 2125-2126. Viral genomes described herein may comprise a sequence selected from SEQ ID NO: 1990-2075, 2137-2168, 2171-2237 and 2260-2321.

Viral genomes described herein may comprise more than one antibody polynucleotide. When more than one antibody polynucleotide exists in a viral genome, these antibody polynucleotides may be separated by a linker sequence, with a sequence selected from SEQ ID NO: 1724-1739, 2244-2254 and 2259. In some embodiments, viral genomes described herein comprise a first antibody polynucleotide sequence and a second antibody polynucleotide sequence, wherein each may encode an antibody heavy or light chain or a fragment thereof. In some embodiments, the viral genome comprises more than two antibody polynucleotides.

In some embodiments, a viral genome, when read 5′ to 3′, may encode an antibody heavy chain, at least one linker, and an antibody light chain. This viral genome may be described as comprising a heavy-linker-light configuration.

In some embodiments, a viral genome, when read 5′ to 3′, may encode an antibody light chain, at least one linker, and an antibody heavy chain. This viral genome may be described as comprising a light-linker-heavy configuration.

The viral genomes described herein may be packaged into an AAV particle comprising any AAV serotype known in the art, or selected from VOY101, VOY201, AAVPHP.B (PHP.B), AAVPHP.A (PHP.A), AAVG2B-26, AAVG2B-13, AAVTH1.1-32, AAVTH1.1-35, AAVPHP.B2 (PHP.B2), AAVPHP.B3 (PHP.B3), AAVPHP.N/PHP.B-DGT, AAVPHP.B-EST, AAVPHP.B-GGT, AAVPHP.B-ATP, AAVPHP.B-ATT-T, AAVPHP.B-DGT-T, AAVPHP.B-GGT-T, AAVPHP.B-SGS, AAVPHP.B-AQP, AAVPHP.B-QQP, AAVPHP.B-SNP(3), AAVPHP.B-SNP, AAVPHP.B-QGT, AAVPHP.B-NQT, AAVPHP.B-EGS, AAVPHP.B-SGN, AAVPHP.B-EGT, AAVPHP.B-DST, AAVPHP.B-DST, AAVPHP.B-STP, AAVPHP.B-PQP, AAVPHP.B-SQP, AAVPHP.B-QLP, AAVPHP.B-TMP, AAVPHP.B-TTP, AAVPHP.S/G2A12, AAVG2A15/G2A3 (G2A3), AAVG2B4 (G2B4), AAVG2B5 (G2B5), PHP.S, AAV1, AAV2, AAV2 variants, AAV2G9, AAV3, AAV2/3 variants AAV3a, AAV3b, AAV3-3, AAV4, AAV4-4, AAV5, AAV6, AAV6.1, AAV6.2, AAV6.1.2, AAV7, AAV7.2, AAV8, AAV9, AAV9K449R, AAV9.11, AAV9.13, AAV9.16, AAV9.24, AAV9.45, AAV9.47, AAV9.61, AAV9.68, AAV9.84, AAV9.9, AAV10, AAV11, AAV12, AAV16.3, AAV24.1, AAV27.3, AAV42.12, AAV42-1b, AAV42-2, AAV42-3a, AAV42-3b, AAV42-4, AAV42-5a, AAV42-5b, AAV42-6b, AAV42-8, AAV42-10, AAV42-11, AAV42-12, AAV42-13, AAV42-15, AAV42-aa, AAV43-1, AAV43-12, AAV43-20, AAV43-21, AAV43-23, AAV43-25, AAV43-5, AAV44.1, AAV44.2, AAV44.5, AAV223.1, AAV223.2, AAV223.4, AAV223.5, AAV223.6, AAV223.7, AAV1-7/rh.48, AAV1-8/rh.49, AAV2-15/rh.62, AAV2-3/rh.61, AAV2-4/rh.50, AAV2-5/rh.51, AAV3.1/hu.6, AAV3.1/hu.9, AAV3-9/rh.52, AAV3-11/rh.53, AAV4-8/r11.64, AAV4-9/rh.54, AAV4-19/rh.55, AAV5-3/rh.57, AAV5-22/rh.58, AAV7.3/hu.7, AAV16.8/hu.10, AAV16.12/hu.11, AAV29.3/bb.1, AAV29.5/bb.2, AAV106.1/hu.37, AAV114.3/hu.40, AAV127.2/hu.41, AAV127.5/hu.42, AAV128.3/hu.44, AAV130.4/hu.48, AAV145.1/hu.53, AAV145.5/hu.54, AAV145.6/hu.55, AAV161.10/hu.60, AAV161.6/hu.61, AAV33.12/hu.17, AAV33.4/hu.15, AAV33.8/hu.16, AAV52/hu.19, AAV52.1/hu.20, AAV58.2/hu.25, AAVA3.3, AAVA3.4, AAVA3.5, AAVA3.7, AAVC1, AAVC2, AAVC5, AAV-DJ, AAV-DJ8, AAVF3, AAVF5, AAVH2, AAVrh.72, AAVhu.8, AAVrh.68, AAVrh.70, AAVpi.1, AAVpi.3, AAVpi.2, AAVrh.60, AAVrh.44, AAVrh.65, AAVrh.55, AAVrh.47, AAVrh.69, AAVrh.45, AAVrh.59, AAVhu.12, AAVH6, AAVLK03, AAVH-1/hu.1, AAVH-5/hu.3, AAVLG-10/rh.40, AAVLG-4/rh.38, AAVLG-9/hu.39, AAVN721-8/rh.43, AAVCh.5, AAVCh.5R1, AAVcy.2, AAVcy.3, AAVcy.4, AAVcy.5, AAVCy.5R1, AAVCy.5R2, AAVCy.5R3, AAVCy.5R4, AAVcy.6, AAVhu.1, AAVhu.2, AAVhu.3, AAVhu.4, AAVhu.5, AAVhu.6, AAVhu.7, AAVhu.9, AAVhu.10, AAVhu.11, AAVhu.13, AAVhu.15, AAVhu.16, AAVhu.17, AAVhu.18, AAVhu.20, AAVhu.21, AAVhu.22, AAVhu.23.2, AAVhu.24, AAVhu.25, AAVhu.27, AAVhu.28, AAVhu.29, AAVhu.29R, AAVhu.31, AAVhu.32, AAVhu.34, AAVhu.35, AAVhu.37, AAVhu.39, AAVhu.40, AAVhu.41, AAVhu.42, AAVhu.43, AAVhu.44, AAVhu.44R1, AAVhu.44R2, AAVhu.44R3, AAVhu.45, AAVhu.46, AAVhu.47, AAVhu.48, AAVhu.48R1, AAVhu.48R2, AAVhu.48R3, AAVhu.49, AAVhu.51, AAVhu.52, AAVhu.54, AAVhu.55, AAVhu.56, AAVhu.57, AAVhu.58, AAVhu.60, AAVhu.61, AAVhu.63, AAVhu.64, AAVhu.66, AAVhu.67, AAVhu.14/9, AAVhu.t 19, AAVrh.2, AAVrh.2R, AAVrh.8, AAVrh.8R, AAVrh.10, AAVrh.12, AAVrh.13, AAVrh.13R, AAVrh.14, AAVrh.17, AAVrh.18, AAVrh.19, AAVrh.20, AAVrh.21, AAVrh.22, AAVrh.23, AAVrh.24, AAVrh.25, AAVrh.31, AAVrh.32, AAVrh.33, AAVrh.34, AAVrh.35, AAVrh.36, AAVrh.37, AAVrh.37R2, AAVrh.38, AAVrh.39, AAVrh.40, AAVrh.46, AAVrh.48, AAVrh.48.1, AAVrh.48.1.2, AAVrh.48.2, AAVrh.49, AAVrh.51, AAVrh.52, AAVrh.53, AAVrh.54, AAVrh.56, AAVrh.57, AAVrh.58, AAVrh.61, AAVrh.64, AAVrh.64R1, AAVrh.64R2, AAVrh.67, AAVrh.73, AAVrh.74, AAVrh8R, AAVrh8R A586R mutant, AAVrh8R R533A mutant, AAAV, BAAV, caprine AAV, bovine AAV, AAVhE1.1, AAVhEr1.5, AAVhER1.14, AAVhEr1.8, AAVhEr1.16, AAVhEr1.18, AAVhEr1.35, AAVhEr1.7, AAVhEr1.36, AAVhEr2.29, AAVhEr2.4, AAVhEr2.16, AAVhEr2.30, AAVhEr2.31, AAVhEr2.36, AAVhER1.23, AAVhEr3.1, AAV2.5T, AAV-PAEC, AAV-LK01, AAV-LK02, AAV-LK03, AAV-LK04, AAV-LK05, AAV-LK06, AAV-LK07, AAV-LK08, AAV-LK09, AAV-LK10, AAV-LK11, AAV-LK12, AAV-LK13, AAV-LK14, AAV-LK15, AAV-LK16, AAV-LK17, AAV-LK18, AAV-LK19, AAV-PAEC2, AAV-PAEC4, AAV-PAEC6, AAV-PAEC7, AAV-PAEC8, AAV-PAEC11, AAV-PAEC12, AAV-2-pre-miRNA-101, AAV-8h, AAV-8b, AAV-h, AAV-b, AAV SM 10-2, AAV Shuffle 100-1, AAV Shuffle 100-3, AAV Shuffle 100-7, AAV Shuffle 10-2, AAV Shuffle 10-6, AAV Shuffle 10-8, AAV Shuffle 100-2, AAV SM 10-1, AAV SM 10-8, AAV SM 100-3, AAV SM 100-10, BNP61 AAV, BNP62 AAV, BNP63 AAV, AAVrh.50, AAVrh.43, AAVrh.62, AAVrh.48, AAVhu.19, AAVhu.11, AAVhu.53, AAV4-8/rh.64, AAVLG-9/hu.39, AAV54.5/hu.23, AAV54.2/hu.22, AAV54.7/hu.24, AAV54.1/hu.21, AAV54.4R/hu.27, AAV46.2/hu.28, AAV46.6/hu.29, AAV128.1/hu.43, true type AAV (ttAAV), UPENN AAV 10, Japanese AAV 10 serotypes, AAV CBr-7.1, AAV CBr-7.10, AAV CBr-7.2, AAV CBr-7.3, AAV CBr-7.4, AAV CBr-7.5, AAV CBr-7.7, AAV CBr-7.8, AAV CBr-B7.3, AAV CBr-B7.4, AAV CBr-E1, AAV CBr-E2, AAV CBr-E3, AAV CBr-E4, AAV CBr-E5, AAV CBr-e5, AAV CBr-E6, AAV CBr-E7, AAV CBr-E8, AAV CHt-1, AAV CHt-2, AAV CHt-3, AAV CHt-6.1, AAV CHt-6.10, AAV CHt-6.5, AAV CHt-6.6, AAV CHt-6.7, AAV CHt-6.8, AAV CHt-P1, AAV CHt-P2, AAV CHt-P5, AAV CHt-P6, AAV CHt-P8, AAV CHt-P9, AAV CKd-1, AAV CKd-10, AAV CKd-2, AAV CKd-3, AAV CKd-4, AAV CKd-6, AAV CKd-7, AAV CKd-8, AAV CKd-B1, AAV CKd-B2, AAV CKd-B3, AAV CKd-B4, AAV CKd-B5, AAV CKd-B6, AAV CKd-B7, AAV CKd-B8, AAV CKd-H1, AAV CKd-H2, AAV CKd-H3, AAV CKd-H4, AAV CKd-H5, AAV CKd-H6, AAV CKd-N3, AAV CKd-N4, AAV CKd-N9, AAV CLg-F1, AAV CLg-F2, AAV CLg-F3, AAV CLg-F4, AAV CLg-F5, AAV CLg-F6, AAV CLg-F7, AAV CLg-F8, AAV CLv-1, AAV CLv1-1, AAV Clv1-10, AAV CLv1-2, AAV CLv-12, AAV CLv1-3, AAV CLv-13, AAV CLv1-4, AAV Clv1-7, AAV Clv1-8, AAV Clv1-9, AAV CLv-2, AAV CLv-3, AAV CLv-4, AAV CLv-6, AAV CLv-8, AAV CLv-D1, AAV CLv-D2, AAV CLv-D3, AAV CLv-D4, AAV CLv-D5, AAV CLv-D6, AAV CLv-D7, AAV CLv-D8, AAV CLv-E1, AAV CLv-K1, AAV CLv-K3, AAV CLv-K6, AAV CLv-L4, AAV CLv-L5, AAV CLv-L6, AAV CLv-M1, AAV CLv-M11, AAV CLv-M2, AAV CLv-M5, AAV CLv-M6, AAV CLv-M7, AAV CLv-M8, AAV CLv-M9, AAV CLv-R1, AAV CLv-R2, AAV CLv-R3, AAV CLv-R4, AAV CLv-R5, AAV CLv-R6, AAV CLv-R7, AAV CLv-R8, AAV CLv-R9, AAV CSp-1, AAV CSp-10, AAV CSp-11, AAV CSp-2, AAV CSp-3, AAV CSp-4, AAV CSp-6, AAV CSp-7, AAV CSp-8, AAV CSp-8.10, AAV CSp-8.2, AAV CSp-8.4, AAV CSp-8.5, AAV CSp-8.6, AAV CSp-8.7, AAV CSp-8.8, AAV CSp-8.9, AAV CSp-9, AAV.hu.48R3, AAV.VR-355, AAV3B, AAV4, AAV5, AAVF1/HSC1, AAVF11/HSC11, AAVF12/HSC12, AAVF13/HSC13, AAVF14/HSC14, AAVF15/HSC15, AAVF16/HSC16, AAVF17/HSC17, AAVF2/HSC2, AAVF3/HSC3, AAVF4/HSC4, AAVF5/HSC5, AAVF6/HSC6, AAVF7/HSC7, AAVF8/HSC8, and/or AAVF9/HSC9 and variants thereof.

In some embodiments, the capsid of the AAV particle is one of VOY101, PHP.B, AAV9, AAV9K449, AAV1, AAV2, VOY201, AAV2 variant or AAV2/3 variant.

AAV particles described herein may be prepared as a pharmaceutical composition. In some embodiments, the pharmaceutical composition may be administered to a subject. In some embodiments, a method of producing a functional antibody in a subject may comprise administration of a pharmaceutical composition described herein to the subject. In some embodiments, the functional antibody may be encoded by one or more antibody polynucleotides of a viral genome described herein, packaged into an AAV particle. In some embodiments, the functional antibody may be encoded by two different viral genomes, packaged into separate AAV particles. The functional antibody may be expressed in a target cell or tissue in a range from 0.001 μg/mL to 100 mg/mL.

Pharmaceutical compositions described herein may be used in a method of treating tauopathy, wherein a therapeutically effective amount of a pharmaceutical composition described herein is administered to a subject in need. The tauopathy may be any one of Alzheimer's disease (AD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Frontotemporal lobar degeneration (FTLD), Frontotemporal dementia, chronic traumatic encephalopathy (CTE), Progressive Supranuclear Palsy (PSP), Down's syndrome, Pick's disease, Corticobasal degeneration (CBD), Corticobasal syndrome, Amyotrophic lateral sclerosis (ALS), Prion diseases, Creutzfeldt-Jakob disease (CJD), Multiple system atrophy, Tangle-only dementia, and Progressive subcortical gliosis or other tau associated disease.

Pharmaceutical compositions described herein may be used in a method of preventing tauopathy, wherein a therapeutically effective amount of a pharmaceutical composition described herein is administered to a subject in need. The tauopathy may be any one of Alzheimer's disease (AD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Frontotemporal lobar degeneration (FTLD). Frontotemporal dementia, chronic traumatic encephalopathy (CTE), Progressive Supranuclear Palsy (PSP), Down's syndrome, Pick's disease. Corticobasal degeneration (CBD), Corticobasal syndrome. Amyotrophic lateral sclerosis (ALS), Prion diseases, Creutzfeldt-Jakob disease (CJD), Multiple system atrophy, Tangle-only dementia, and Progressive subcortical gliosis or other tau associated disease.

The method of delivery of the pharmaceutical composition described herein to a subject in need may comprise any delivery route known in the art, including, intravenous (into a vein), intramuscular (into a muscle), intraparenchymal (into the substance of a tissue, e.g., brain), enteral (into the intestine), gastroenteral, epidural (into the dura mater), oral (by way of the mouth), transdermal, intracerebral (into the cerebrum), intracerebroventricular (into the cerebral ventricles), epicutaneous (application onto the skin), intradermal, (into the skin itself), subcutaneous (under the skin), nasal administration (through the nose), intravenous bolus, intravenous drip, intra-arterial (into an artery), intracardiac (into the heart), intraosseous infusion (into the bone marrow), intrathecal (into the spinal canal), intraperitoneal, (infusion or injection into the peritoneum), intravesical infusion, intravitreal, (through the eye), intracavernous injection (into a pathologic cavity) intracavitary (into the base of the penis), intravaginal administration, intrauterine, extra-amniotic administration, transdermal (diffusion through the intact skin for systemic distribution), transmucosal (diffusion through a mucous membrane), transvaginal, insufflation (snorting), sublingual, sublabial, enema, eye drops (onto the conjunctiva), or in ear drops, auricular (in or by way of the ear), buccal (directed toward the cheek), conjunctival, cutaneous, dental (to a tooth or teeth), electro-osmosis, endocervical, endosinusial, endotracheal, extracorporeal, hemodialysis, infiltration, interstitial, intra-abdominal, intra-amniotic, intra-articular, intrabiliary, intrabronchial, intrabursal, intracartilaginous (within a cartilage), intracaudal (within the cauda equine), intracisternal (within the cisterna magna cerebellomedularis), intracorneal (within the cornea), dental intracoronal, intracoronary (within the coronary arteries), intracorporus cavernosum (within the dilatable spaces of the corporus cavernosa of the penis), intradiscal (within a disc), intraductal (within a duct of a gland), intraduodenal (within the duodenum), intradural (within or beneath the dura), intraepidermal (to the epidermis), intraesophageal (to the esophagus), intragastric (within the stomach), intragingival (within the gingivae), intraileal (within the distal portion of the small intestine), intralesional (within or introduced directly to a localized lesion), intraluminal (within a lumen of a tube), intralymphatic (within the lymph), intramedullary (within the marrow cavity of a bone), intrameningeal (within the meninges), intramyocardial (within the myocardium), intraocular (within the eye), intraovarian (within the ovary), intrapericardial (within the pericardium), intrapleural (within the pleura), intraprostatic (within the prostate gland), intrapulmonary (within the lungs or its bronchi), intrasinal (within the nasal or periorbital sinuses), intraspinal (within the vertebral column), intrasynovial (within the synovial cavity of a joint), intratendinous (within a tendon), intratesticular (within the testicle), intrathecal (within the cerebrospinal fluid at any level of the cerebrospinal axis), intrathoracic (within the thorax), intratubular (within the tubules of an organ), intratumor (within a tumor), intratympanic (within the aurus media), intravascular (within a vessel or vessels), intraventricular (within a ventricle), iontophoresis (by means of electric current where ions of soluble salts migrate into the tissues of the body), irrigation (to bathe or flush open wounds or body cavities), laryngeal (directly upon the larynx), nasogastric (through the nose and into the stomach), occlusive dressing technique (topical route administration which is then covered by a dressing which occludes the area), ophthalmic (to the external eye), oropharyngeal (directly to the mouth and pharynx), parenteral, percutaneous, periarticular, peridural, perineural, periodontal, rectal, respiratory (within the respiratory tract by inhaling orally or nasally for local or systemic effect), retrobulbar (behind the pons or behind the eyeball), soft tissue, subarachnoid, subconjunctival, submucosal, topical, transplacental (through or across the placenta), transtracheal (through the wall of the trachea), transtympanic (across or through the tympanic cavity), ureteral (to the ureter), urethral (to the urethra), vaginal, caudal block, diagnostic, nerve block, biliary perfusion, cardiac perfusion, photopheresis and spinal.

In some embodiments AAV particles or pharmaceutical compositions described herein are delivered by intramuscular administration. In some embodiments AAV particles or pharmaceutical compositions described herein are delivered by intravascular administration. In some embodiments AAV particles or pharmaceutical compositions described herein are delivered by intravenous administration. In some embodiments AAV particles or pharmaceutical compositions described herein are delivered by intracerebroventricular administration. In some embodiments AAV particles or pharmaceutical compositions described herein are delivered by intraparenchymal administration. In some embodiments AAV particles or pharmaceutical compositions described herein are delivered by intrathecal administration.

DETAILED DESCRIPTION I. Compositions

According to the present disclosure, compositions for delivering functional anti-tau antibodies and/or antibody-based compositions by adeno-associated viruses (AAVs) are provided. AAV particles may be provided via any of several routes of administration, to a cell, tissue, organ, or organism, in vivo, ex vivo, or in vitro.

As used herein, an “AAV particle” is a virus which comprises a viral genome with at least one payload region and at least one inverted terminal repeat (ITR) region.

As used herein, “viral genome” or “vector genome” refers to the nucleic acid sequence(s) encapsulated in an AAV particle. Viral genomes comprise at least one payload region encoding polypeptides, e.g., antibodies, antibody-based compositions or fragments thereof.

As used herein, a “payload” or “payload region” is any nucleic acid molecule which encodes one or more polypeptides. At a minimum, a payload region comprises nucleic acid sequences that encode an antibody, an antibody-based composition, or a fragment thereof, but may also optionally comprise one or more functional or regulatory elements to facilitate transcriptional expression and/or polypeptide translation.

As used herein, “VL” and “VH” refer to components of a light chain or heavy chain of an antibody, respectively, or a fragment thereof. In some embodiments, “VL” and “VH” refer to the variable regions of the light or heavy chain of an antibody, respectively, or a fragment thereof. In another embodiment, “VL” and “VH” may also embrace a constant region of a light or heavy chain of an antibody, or a fragment thereof. In another embodiment, “VL” and “VH” may embrace the entirety of an antibody light chain or heavy chain, respectively.

In some embodiments, AAV particles, viral genomes and/or payloads, and the methods of their use may be as described in WO2017189963, the contents of which are herein incorporated by reference in their entirety.

The nucleic acid sequences and polypeptides disclosed herein may be engineered to contain modular elements and/or sequence motifs assembled to enable expression of the antibodies or antibody-based compositions. In some embodiments, the nucleic acid sequence comprising the payload region may comprise one or more of a promoter region, an intron, a Kozak sequence, an enhancer, or a polyadenylation sequence. Payload regions typically encode antibodies or antibody-based compositions, which may include an antibody heavy chain domain, an antibody light chain domain, both antibody heavy and light chain domains, or fragments of the foregoing in combination with each other or in combination with other polypeptide moieties. In some cases, payload regions may also encode one or more linkers or joining regions between antibody heavy and light chain domains or fragments. The order of expression, structural position, or concatemer count (heavy chain, light chain, or linker) may be different within or among different payload regions. The identity, position and number of linkers expressed by payload regions may also vary.

The payload regions may be delivered to one or more target cells, tissues, organs, or organisms within the viral genome of an AAV particle.

Adeno-Associated Viruses (AAVs) and AAV Particles

Adeno-associated viruses (AAV) are small non-enveloped icosahedral capsid viruses of the Parvoviridae family characterized by a single stranded DNA viral genome. Parvoviridae family viruses consist of two subfamilies: Parvovirinae, which infect vertebrates, and Densovirinae, which infect invertebrates. The Parvoviridae family comprises the Dependovirus genus which includes AAV, capable of replication in vertebrate hosts including, but not limited to, human, primate, bovine, canine, equine, and ovine species.

The parvoviruses and other members of the Parvoviridae family are generally described in Kenneth I. Berns, “Parvoviridae: The Viruses and Their Replication,” Chapter 69 in FIELDS VIROLOGY (3d Ed. 1996), the contents of which are incorporated by reference in their entirety.

AAV have proven to be useful as a biological tool due to their relatively simple structure, their ability to infect a wide range of cells (including quiescent and dividing cells) without integration into the host genome and without replicating, and their relatively benign immunogenic profile. The genome of the virus may be manipulated to contain a minimum of components for the assembly of a functional recombinant virus, or viral particle, which is loaded with or engineered to target a particular tissue and express or deliver a desired payload.

The wild-type AAV vector genome is a linear, single-stranded DNA (ssDNA) molecule approximately 5,000 nucleotides (nt) in length. Inverted terminal repeats (ITRs) traditionally cap the viral genome at both the 5′ and the 3′ end, providing origins of replication for the viral genome. While not wishing to be bound by theory, an AAV viral genome typically comprises two ITR sequences. These ITRs have a characteristic T-shaped hairpin structure defined by a self-complementary region (145 nt in wild-type AAV) at the 5′ and 3′ ends of the ssDNA which form an energetically stable double stranded region. The double stranded hairpin structures comprise multiple functions including, but not limited to, acting as an origin for DNA replication by functioning as primers for the endogenous DNA polymerase complex of the host viral replication cell.

The wild-type AAV viral genome further comprises nucleotide sequences for two open reading frames, one for the four non-structural Rep proteins (Rep78, Rep68, Rep52, Rep40, encoded by Rep genes) and one for the three capsid, or structural, proteins (VP1, VP2, VP3, encoded by capsid genes or Cap genes). The Rep proteins are important for replication and packaging, while the capsid proteins are assembled to create the protein shell of the AAV, or AAV capsid. Alternative splicing and alternate initiation codons and promoters result in the generation of four different Rep proteins from a single open reading frame and the generation of three capsid proteins from a single open reading frame. Though it varies by AAV serotype, as a non-limiting example, for AAV9/hu.14 (SEQ ID NO: 123 of U.S. Pat. No. 7,906,111, the contents of which are herein incorporated by reference in their entirety) VP1 refers to amino acids 1-736, VP2 refers to amino acids 138-736, and VP3 refers to amino acids 203-736. In other words, VP1 is the full-length capsid sequence, while VP2 and VP3 are shorter components of the whole. As a result, changes in the sequence in the VP3 region, are also changes to VP1 and VP2, however, the percent difference as compared to the parent sequence will be greatest for VP3 since it is the shortest sequence of the three. Though described here in relation to the amino acid sequence, the nucleic acid sequence encoding these proteins can be similarly described. Together, the three capsid proteins assemble to create the AAV capsid protein. While not wishing to be bound by theory, the AAV capsid protein typically comprises a molar ratio of 1:1:10 of VP1:VP2:VP3. As used herein, an “AAV serotype” is defined primarily by the AAV capsid. In some instances, the ITRs are also specifically described by the AAV serotype (e.g., AAV2/9).

For use as a biological tool, the wild-type AAV viral genome can be modified to replace the rep/cap sequences with a nucleic acid sequence comprising a payload region with at least one ITR region. Typically, in recombinant AAV viral genomes there are two ITR regions. The rep/cap sequences can be provided in trans during production to generate AAV particles.

In addition to the encoded heterologous payload, AAV vectors may comprise the viral genome, in whole or in part, of any naturally occurring and/or recombinant AAV serotype nucleotide sequence or variant. AAV variants may have sequences of significant homology at the nucleic acid (genome or capsid) and amino acid levels (capsids), to produce constructs which are generally physical and functional equivalents, replicate by similar mechanisms, and assemble by similar mechanisms. Chiorini et al., J. Vir. 71: 6823-33(1997); Srivastava et al., J. Vir. 45:555-64 (1983); Chiorini et al., J. Vir. 73:1309-1319 (1999); Rutledge et al., J. Vir. 72:309-319 (1998); and Wu et al., J. Vir. 74: 8635-47 (2000), the contents of each of which are incorporated herein by reference in their entirety.

In some embodiments, AAV particles of the present disclosure are recombinant AAV viral vectors which are replication defective and lacking sequences encoding functional Rep and Cap proteins within their viral genome. These defective AAV vectors may lack most or all parental coding sequences and essentially carry only one or two AAV ITR sequences and the nucleic acid of interest for delivery to a cell, a tissue, an organ, or an organism.

In some embodiments, the viral genome of the AAV particles of the present disclosure comprise at least one control element which provides for the replication, transcription, and translation of a coding sequence encoded therein. Not all of the control elements need always be present as long as the coding sequence is capable of being replicated, transcribed, and/or translated in an appropriate host cell. Non-limiting examples of expression control elements include sequences for transcription initiation and/or termination, promoter and/or enhancer sequences, efficient RNA processing signals such as splicing and polyadenylation signals, sequences that stabilize cytoplasmic mRNA, sequences that enhance translation efficacy (e.g., Kozak consensus sequence), sequences that enhance protein stability, and/or sequences that enhance protein processing and/or secretion.

According to the present disclosure, AAV particles for use in therapeutics and/or diagnostics comprise a virus that has been distilled or reduced to the minimum components necessary for transduction of a nucleic acid payload or cargo of interest. In this manner, AAV particles are engineered as vehicles for specific delivery while lacking the deleterious replication and/or integration features found in wild-type viruses.

AAV vectors of the present disclosure may be produced recombinantly and may be based on adeno-associated virus (AAV) parent or reference sequences. As used herein, a “vector” is any molecule or moiety which transports, transduces, or otherwise acts as a carrier of a heterologous molecule such as the nucleic acids described herein.

In addition to single stranded AAV viral genomes (e.g., ssAAVs), the present disclosure also provides for self-complementary AAV (scAAVs) viral genomes, scAAV vector genomes contain DNA strands which anneal together to form double stranded DNA. By skipping second strand synthesis, scAAVs allow for rapid expression in the transduced cell.

In some embodiments, the AAV particle of the present disclosure is an scAAV.

In some embodiments, the AAV particle of the present disclosure is an ssAAV.

Methods for producing and/or modifying AAV particles are disclosed in the art such as pseudotyped AAV vectors (PCT Patent Publication Nos. WO200028004; WO200123001; WO2004112727; WO2005005610; and WO2005072364, the content of each of which is incorporated herein by reference in its entirety).

AAV particles may be modified to enhance the efficiency of delivery. Such modified AAV particles can be packaged efficiently and be used to successfully infect the target cells at high frequency and with minimal toxicity. In some embodiments, the capsids of the AAV particles are engineered according to the methods described in US Publication Number US20130195801, the contents of which are incorporated herein by reference in their entirety.

In some embodiments, the AAV particles comprising a payload region encoding the polypeptides may be introduced into mammalian cells.

AAV Serotypes

AAV particles of the present disclosure may comprise or be derived from any natural or recombinant AAV serotype. According to the present disclosure, the AAV particles may utilize or be based on a serotype or include a peptide selected from any of the following VOY101, VOY201, AAVPHP.B (PHP.B), AAVPHP.A (PHP.A), AAVG2B-26, AAVG2B-13, AAVTH1.1-32, AAVTH1.1-35, AAVPHP.B2 (PHP.B2), AAVPHP.B3 (PHP.B3), AAVPHP.N/PHP.B-DGT, AAVPHP.B-EST, AAVPHP.B-GGT, AAVPHP.B-ATP, AAVPHP.B-ATT-T, AAVPHP.B-DGT-T, AAVPHP.B-GGT-T, AAVPHP.B-SGS, AAVPHP.B-AQP, AAVPHP.B-QQP, AAVPHP.B-SNP(3), AAVPHP.B-SNP, AAVPHP.B-QGT, AAVPHP.B-NQT, AAVPHP.B-EGS, AAVPHP.B-SGN, AAVPHP.B-EGT, AAVPHP.B-DST, AAVPHP.B-DST, AAVPHP.B-STP, AAVPHP.B-PQP, AAVPHP.B-SQP, AAVPHP.B-QLP, AAVPHP.B-TMP, AAVPHP.B-TTP, AAVPHP.S/G2A12, AAVG2A15/G2A3 (G2A3), AAVG2B4 (G2B4), AAVG2B5 (G2B5), PHP.S, AAV1, AAV2, AAV2G9, AAV3, AAV3a, AAV3b, AAV3-3, AAV4, AAV4-4, AAV5, AAV6, AAV6.1, AAV6.2, AAV6.1.2, AAV7, AAV7.2, AAV8, AAV9, AAV9K449R, AAV9.11, AAV9.13, AAV9.16, AAV9.24, AAV9.45, AAV9.47, AAV9.61, AAV9.68, AAV9.84, AAV9.9, AAV10, AAV11, AAV12, AAV16.3, AAV24.1, AAV27.3, AAV42.12, AAV42-1b, AAV42-2, AAV42-3a, AAV42-3b, AAV42-4, AAV42-5a, AAV42-5b, AAV42-6b, AAV42-8, AAV42-10, AAV42-11, AAV42-12, AAV42-13, AAV42-15, AAV42-aa, AAV43-1, AAV43-12, AAV43-20, AAV43-21, AAV43-23, AAV43-25, AAV43-5, AAV44.1, AAV44.2, AAV44.5, AAV223.1, AAV223.2, AAV223.4, AAV223.5, AAV223.6, AAV223.7, AAV1-7/rh.48, AAV1-8/rh.49, AAV2-15/rh.62, AAV2-3/rh.61, AAV2-4/rh.50, AAV2-5/rh.51, AAV3.1/hu.6, AAV3.1/hu.9, AAV3-9/rh.52, AAV3-11/rh.53, AAV4-8/r11.64, AAV4-9/rh.54, AAV4-19/rh.55, AAV5-3/rh.57, AAV5-22/rh.58, AAV7.3/hu.7, AAV16.8/hu.10, AAV16.12/hu.11, AAV29.3/bb.1, AAV29.5/bb.2, AAV106.1/hu.37, AAV114.3/hu.40, AAV127.2/hu.41, AAV127.5/hu.42, AAV128.3/hu.44, AAV130.4/hu.48, AAV145.1/hu.53, AAV145.5/hu.54, AAV145.6/hu.55, AAV161.10/hu.60, AAV161.6/hu.61, AAV33.12/hu.17, AAV33.4/hu.15, AAV33.8/hu.16, AAV52/hu.19, AAV52.1/hu.20, AAV58.2/hu.25, AAVA3.3, AAVA3.4, AAVA3.5, AAVA3.7, AAVC1, AAVC2, AAVC5, AAV-DJ, AAV-DJ8, AAVF3, AAVF5, AAVH2, AAVrh.72, AAVhu.8, AAVrh.68, AAVrh.70, AAVpi.1, AAVpi.3, AAVpi.2, AAVrh.60, AAVrh.44, AAVrh.65, AAVrh.55, AAVrh.47, AAVrh.69, AAVrh.45, AAVrh.59, AAVhu.12, AAVH6, AAVLK03, AAVH-1/hu.1, AAVH-5/hu.3, AAVLG-10/rh.40, AAVLG-4/rh.38, AAVLG-9/hu.39, AAVN721-8/rh.43, AAVCh.5, AAVCh.5R1, AAVcy.2, AAVcy.3, AAVcy.4, AAVcy.5, AAVCy.5R1, AAVCy.5R2, AAVCy.5R3, AAVCy.5R4, AAVcy.6, AAVhu.1, AAVhu.2, AAVhu.3, AAVhu.4, AAVhu.5, AAVhu.6, AAVhu.7, AAVhu.9, AAVhu.10, AAVhu.11, AAVhu.13, AAVhu.15, AAVhu.16, AAVhu.17, AAVhu.18, AAVhu.20, AAVhu.21, AAVhu.22, AAVhu.23.2, AAVhu.24, AAVhu.25, AAVhu.27, AAVhu.28, AAVhu.29, AAVhu.29R, AAVhu.31, AAVhu.32, AAVhu.34, AAVhu.35, AAVhu.37, AAVhu.39, AAVhu.40, AAVhu.41, AAVhu.42, AAVhu.43, AAVhu.44, AAVhu.44R1, AAVhu.44R2, AAVhu.44R3, AAVhu.45, AAVhu.46, AAVhu.47, AAVhu.48, AAVhu.48R1, AAVhu.48R2, AAVhu.48R3, AAVhu.49, AAVhu.51, AAVhu.52, AAVhu.54, AAVhu.55, AAVhu.56, AAVhu.57, AAVhu.58, AAVhu.60, AAVhu.61, AAVhu.63, AAVhu.64, AAVhu.66, AAVhu.67, AAVhu.14/9, AAVhu.t 19, AAVrh.2, AAVrh.2R, AAVrh.8, AAVrh.8R, AAVrh.10, AAVrh.12, AAVrh.13, AAVrh.13R, AAVrh.14, AAVrh.17, AAVrh.18, AAVrh.19, AAVrh.20, AAVrh.21, AAVrh.22, AAVrh.23, AAVrh.24, AAVrh.25, AAVrh.31, AAVrh.32, AAVrh.33, AAVrh.34, AAVrh.35, AAVrh.36, AAVrh.37, AAVrh.37R2, AAVrh.38, AAVrh.39, AAVrh.40, AAVrh.46, AAVrh.48, AAVrh.48.1, AAVrh.48.1.2, AAVrh.48.2, AAVrh.49, AAVrh.51, AAVrh.52, AAVrh.53, AAVrh.54, AAVrh.56, AAVrh.57, AAVrh.58, AAVrh.61, AAVrh.64, AAVrh.64R1, AAVrh.64R2, AAVrh.67, AAVrh.73, AAVrh.74, AAVrh8R, AAVrh8R A586R mutant, AAVrh8R R533A mutant, AAAV, BAAV, caprine AAV, bovine AAV, AAVhE1.1, AAVhEr1.5, AAVhER1.14, AAVhEr1.8, AAVhEr1.16, AAVhEr1.18, AAVhEr1.35, AAVhEr1.7, AAVhEr1.36, AAVhEr2.29, AAVhEr2.4, AAVhEr2.16, AAVhEr2.30, AAVhEr2.31, AAVhEr2.36, AAVhER1.23, AAVhEr3.1, AAV2.5T, AAV-PAEC, AAV-LK01, AAV-LK02, AAV-LK03, AAV-LK04, AAV-LK05, AAV-LK06, AAV-LK07, AAV-LK08, AAV-LK09, AAV-LK10, AAV-LK11, AAV-LK12, AAV-LK13, AAV-LK14, AAV-LK15, AAV-LK16, AAV-LK17, AAV-LK18, AAV-LK19, AAV-PAEC2, AAV-PAEC4, AAV-PAEC6, AAV-PAEC7, AAV-PAEC8, AAV-PAEC11, AAV-PAEC12, AAV-2-pre-miRNA-101, AAV-8h, AAV-8b, AAV-h, AAV-b, AAV SM 10-2, AAV Shuffle 100-1, AAV Shuffle 100-3, AAV Shuffle 100-7, AAV Shuffle 10-2, AAV Shuffle 10-6, AAV Shuffle 10-8, AAV Shuffle 100-2, AAV SM 10-1, AAV SM 10-8, AAV SM 100-3, AAV SM 100-10, BNP61 AAV, BNP62 AAV, BNP63 AAV, AAVrh.50, AAVrh.43, AAVrh.62, AAVrh.48, AAVhu.19, AAVhu.11, AAVhu.53, AAV4-8/rh.64, AAVLG-9/hu.39, AAV54.5/hu.23, AAV54.2/hu.22, AAV54.7/hu.24, AAV54.1/hu.21, AAV54.4R/hu.27, AAV46.2/hu.28, AAV46.6/hu.29, AAV128.1/hu.43, true type AAV (ttAAV), UPENN AAV 10, Japanese AAV 10 serotypes, AAV CBr-7.1, AAV CBr-7.10, AAV CBr-7.2, AAV CBr-7.3, AAV CBr-7.4, AAV CBr-7.5, AAV CBr-7.7, AAV CBr-7.8, AAV CBr-B7.3, AAV CBr-B7.4, AAV CBr-E1, AAV CBr-E2, AAV CBr-E3, AAV CBr-E4, AAV CBr-E5, AAV CBr-e5, AAV CBr-E6, AAV CBr-E7, AAV CBr-E8, AAV CHt-1, AAV CHt-2, AAV CHt-3, AAV CHt-6.1, AAV CHt-6.10, AAV CHt-6.5, AAV CHt-6.6, AAV CHt-6.7, AAV CHt-6.8, AAV CHt-P1, AAV CHt-P2, AAV CHt-P5, AAV CHt-P6, AAV CHt-P8, AAV CHt-P9, AAV CKd-1, AAV CKd-10, AAV CKd-2, AAV CKd-3, AAV CKd-4, AAV CKd-6, AAV CKd-7, AAV CKd-8, AAV CKd-B1, AAV CKd-B2, AAV CKd-B3, AAV CKd-B4, AAV CKd-B5, AAV CKd-B6, AAV CKd-B7, AAV CKd-B8, AAV CKd-H1, AAV CKd-H2, AAV CKd-H3, AAV CKd-H4, AAV CKd-H5, AAV CKd-H6, AAV CKd-N3, AAV CKd-N4, AAV CKd-N9, AAV CLg-F1, AAV CLg-F2, AAV CLg-F3, AAV CLg-F4, AAV CLg-F5, AAV CLg-F6, AAV CLg-F7, AAV CLg-F8, AAV CLv-1, AAV CLv-1, AAV Clv1-10, AAV CLv1-2, AAV CLv-12, AAV CLv1-3, AAV CLv-13, AAV CLv1-4, AAV Clv1-7, AAV Clv1-8, AAV Clv1-9, AAV CLv-2, AAV CLv-3, AAV CLv-4, AAV CLv-6, AAV CLv-8, AAV CLv-D1, AAV CLv-D2, AAV CLv-D3, AAV CLv-D4, AAV CLv-D5, AAV CLv-D6, AAV CLv-D7, AAV CLv-D8, AAV CLv-E1, AAV CLv-K1, AAV CLv-K3, AAV CLv-K6, AAV CLv-L4, AAV CLv-L5, AAV CLv-L6, AAV CLv-M1, AAV CLv-M11, AAV CLv-M2, AAV CLv-M5, AAV CLv-M6, AAV CLv-M7, AAV CLv-M8, AAV CLv-M9, AAV CLv-R1, AAV CLv-R2, AAV CLv-R3, AAV CLv-R4, AAV CLv-R5, AAV CLv-R6, AAV CLv-R7, AAV CLv-R8, AAV CLv-R9, AAV CSp-1, AAV CSp-10, AAV CSp-11, AAV CSp-2, AAV CSp-3, AAV CSp-4, AAV CSp-6, AAV CSp-7, AAV CSp-8, AAV CSp-8.10, AAV CSp-8.2, AAV CSp-8.4, AAV CSp-8.5, AAV CSp-8.6, AAV CSp-8.7, AAV CSp-8.8, AAV CSp-8.9, AAV CSp-9, AAV.hu.48R3, AAV.VR-355, AAV3B, AAV4, AAV5, AAVF1/HSC1, AAVF11/HSC11, AAVF12/HSC12, AAVF13/HSC13, AAVF14/HSC14, AAVF15/HSC15, AAVF16/HSC16, AAVF17/HSC17, AAVF2/HSC2, AAVF3/HSC3, AAVF4/HSC4, AAVF5/HSC5, AAVF6/HSC6, AAVF7/HSC7, AAVF8/HSC8, and/or AAVF9/HSC9 and variants thereof.

In some embodiments, the AAV serotype may be, or have, a sequence as described in United States Publication No. US20030138772, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to: AAV1 (SEQ ID NO: 6 and 64 of US20030138772), AAV2 (SEQ ID NO: 7 and 70 of US20030138772), AAV3 (SEQ ID NO: 8 and 71 of US20030138772), AAV4 (SEQ ID NO: 63 of US20030138772), AAV5 (SEQ ID NO: 114 of US20030138772), AAV6 (SEQ ID NO: 65 of US20030138772), AAV7 (SEQ ID NO: 1-3 of US20030138772), AAV8 (SEQ ID NO: 4 and 95 of US20030138772), AAV9 (SEQ ID NO: 5 and 100 of US20030138772), AAV10 (SEQ ID NO: 117 of US20030138772), AAV11 (SEQ ID NO: 118 of US20030138772), AAV12 (SEQ ID NO: 119 of US20030138772), AAVrh10 (amino acids 1 to 738 of SEQ ID NO: 81 of US20030138772), AAV16.3 (US20030138772 SEQ ID NO: 10), AAV29.3/bb.1 (US20030138772 SEQ ID NO: 11), AAV29.4 (US20030138772 SEQ ID NO: 12), AAV29.5/bb.2 (US20030138772 SEQ ID NO: 13), AAV1.3 (US20030138772 SEQ ID NO: 14), AAV13.3 (US20030138772 SEQ ID NO: 15), AAV24.1 (US20030138772 SEQ ID NO: 16), AAV27.3 (US20030138772 SEQ ID NO: 17), AAV7.2 (US20030138772 SEQ ID NO: 18), AAVC1 (US20030138772 SEQ ID NO: 19), AAVC3 (US20030138772 SEQ ID NO: 20), AAVC5 (US20030138772 SEQ ID NO: 21), AAVF1 (US20030138772 SEQ ID NO: 22), AAVF3 (US20030138772 SEQ ID NO: 23), AAVF5 (US20030138772 SEQ ID NO: 24), AAVH6 (US20030138772 SEQ ID NO: 25), AAVH2 (US20030138772 SEQ ID NO: 26), AAV42-8 (US20030138772 SEQ ID NO: 27), AAV42-15 (US20030138772 SEQ ID NO: 28), AAV42-5b (US20030138772 SEQ ID NO: 29), AAV42-1b (US20030138772 SEQ ID NO: 30), AAV42-13 (US20030138772 SEQ ID NO: 31), AAV42-3a (US20030138772 SEQ ID NO: 32), AAV42-4 (US20030138772 SEQ ID NO: 33), AAV42-5a (US20030138772 SEQ ID NO: 34), AAV42-10 (US20030138772 SEQ ID NO: 35), AAV42-3b (US20030138772 SEQ ID NO: 36), AAV42-11 (US20030138772 SEQ ID NO: 37), AAV42-6b (US20030138772 SEQ ID NO: 38), AAV43-1 (US20030138772 SEQ ID NO: 39), AAV43-5 (US20030138772 SEQ ID NO: 40), AAV43-12 (US20030138772 SEQ ID NO: 41), AAV43-20 (US20030138772 SEQ ID NO: 42), AAV43-21 (US20030138772 SEQ ID NO: 43), AAV43-23 (US20030138772 SEQ ID NO: 44), AAV43-25 (US20030138772 SEQ ID NO: 45), AAV44.1 (US20030138772 SEQ ID NO: 46), AAV44.5 (US20030138772 SEQ ID NO: 47), AAV223.1 (US20030138772 SEQ ID NO: 48), AAV223.2 (US20030138772 SEQ ID NO: 49), AAV223.4 (US20030138772 SEQ ID NO: 50), AAV223.5 (US20030138772 SEQ ID NO: 51), AAV223.6 (US20030138772 SEQ ID NO: 52), AAV223.7 (US20030138772 SEQ ID NO: 53), AAVA3.4 (US20030138772 SEQ ID NO: 54), AAVA3.5 (US20030138772 SEQ ID NO: 55), AAVA3.7 (US20030138772 SEQ ID NO: 56), AAVA3.3 (US20030138772 SEQ ID NO: 57), AAV42.12 (US20030138772 SEQ ID NO: 58), AAV44.2 (US20030138772 SEQ ID NO: 59), AAV42-2 (US20030138772 SEQ ID NO: 9), or variants thereof.

In some embodiments, the AAV serotype may be, or have, a sequence as described in United States Publication No. US20150159173, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV2 (SEQ ID NO: 7 and 23 of US20150159173), rh20 (SEQ ID NO: 1 of US20150159173), rh32/33 (SEQ ID NO: 2 of US20150159173), rh39 (SEQ ID NO: 3, 20 and 36 of US20150159173), rh46 (SEQ ID NO: 4 and 22 of US20150159173), rh73 (SEQ ID NO: 5 of US20150159173), rh74 (SEQ ID NO: 6 of US20150159173), AAV6.1 (SEQ ID NO: 29 of US20150159173), rh.8 (SEQ ID NO: 41 of US20150159173), rh.48.1 (SEQ ID NO: 44 of US20150159173), hu.44 (SEQ ID NO: 45 of US20150159173), hu.29 (SEQ ID NO: 42 of US20150159173), hu.48 (SEQ ID NO: 38 of US20150159173), rh54 (SEQ ID NO: 49 of US20150159173), AAV2 (SEQ ID NO: 7 of US20150159173), cy.5 (SEQ ID NO: 8 and 24 of US20150159173), rh.10 (SEQ ID NO: 9 and 25 of US20150159173), rh.13 (SEQ ID NO: 10 and 26 of US20150159173), AAV1 (SEQ ID NO: 11 and 27 of US20150159173), AAV3 (SEQ ID NO: 12 and 28 of US20150159173), AAV6 (SEQ ID NO: 13 and 29 of US20150159173), AAV7 (SEQ ID NO: 14 and 30 of US20150159173), AAV8 (SEQ ID NO: 15 and 31 of US20150159173), hu.13 (SEQ ID NO: 16 and 32 of US20150159173), hu.26 (SEQ ID NO: 17 and 33 of US20150159173), hu.37 (SEQ ID NO: 18 and 34 of US20150159173), hu.53 (SEQ ID NO: 19 and 35 of US20150159173), rh.43 (SEQ ID NO: 21 and 37 of US20150159173), rh2 (SEQ ID NO: 39 of US20150159173), rh.37 (SEQ ID NO: 40 of US20150159173), rh.64 (SEQ ID NO: 43 of US20150159173), rh.48 (SEQ ID NO: 44 of US20150159173), ch.5 (SEQ ID NO 46 of US20150159173), rh.67 (SEQ ID NO: 47 of US20150159173), rh.58 (SEQ ID NO: 48 of US20150159173), or variants thereof including, but not limited to CySR1, CySR2, CySR3, Cy5R4, rh.13R, rh.37R2, rh.2R, rh.8R, rh.48.1, rh.48.2, rh.48.1.2, hu.44R1, hu.44R2, hu.44R3, hu.29R, ch.5R1, rh64R1, rh64R2, AAV6.2, AAV6.1, AAV6.12, hu.48R1, hu.48R2, and hu.48R3.

In some embodiments, the AAV serotype may be, or have, a sequence as described in U.S. Pat. No. 7,198,951, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV9 (SEQ ID NO: 1-3 of U.S. Pat. No. 7,198,951), AAV2 (SEQ ID NO: 4 of U.S. Pat. No. 7,198,951), AAV1 (SEQ ID NO: 5 of U.S. Pat. No. 7,198,951), AAV3 (SEQ ID NO: 6 of U.S. Pat. No. 7,198,951), and AAV8 (SEQ ID NO: 7 of U.S. Pat. No. 7,198,951).

In some embodiments, the AAV serotype may be, or have, a mutation in the AAV9 sequence as described by N Pulicherla et al. (Molecular Therapy 19(6):1070-1078 (2011), herein incorporated by reference in its entirety), such as but not limited to, AAV9.9, AAV9.11, AAV9.13, AAV9.16, AAV9.24, AAV9.45, AAV9.47, AAV9.61, AAV9.68, AAV9.84.

In some embodiments, the AAV serotype may be, or have, a sequence as described in U.S. Pat. No. 6,156,303, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV3B (SEQ ID NO: 1 and 10 of U.S. Pat. No. 6,156,303), AAV6 (SEQ ID NO: 2, 7 and 11 of U.S. Pat. No. 6,156,303), AAV2 (SEQ ID NO: 3 and 8 of U.S. Pat. No. 6,156,303), AAV3A (SEQ ID NO: 4 and 9, of U.S. Pat. No. 6,156,303), or derivatives thereof.

In some embodiments, the AAV serotype may be, or have, a sequence as described in United States Publication No. US20140359799, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV8 (SEQ ID NO: 1 of US20140359799), AAVDJ (SEQ ID NO: 2 and 3 of US20140359799), or variants thereof.

In some embodiments, the serotype may be AAVDJ or a variant thereof, such as AAVDJ8 (or AAV-DJ8), as described by Grimm et al. (Journal of Virology 82(12): 5887-5911 (2008), herein incorporated by reference in its entirety). The amino acid sequence of AAVDJ8 may comprise two or more mutations in order to remove the heparin binding domain (HBD). As a non-limiting example, the AAV-DJ sequence described as SEQ ID NO: 1 in U.S. Pat. No. 7,588,772, the contents of which are herein incorporated by reference in their entirety, may comprise two mutations: (1) R587Q where arginine (R; Arg) at amino acid 587 is changed to glutamine (Q; Gln) and (2) R590T where arginine (R; Arg) at amino acid 590 is changed to threonine (T; Thr). As another non-limiting example, may comprise three mutations: (1) K406R where lysine (K; Lys) at amino acid 406 is changed to arginine (R; Arg), (2) R587Q where arginine (R; Arg) at amino acid 587 is changed to glutamine (Q; Gin) and (3) R590T where arginine (R; Arg) at amino acid 590 is changed to threonine (T; Thr).

In some embodiments, the AAV serotype may be, or have, a sequence of AAV4 as described in International Publication No. WO1998011244, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to AAV4 (SEQ ID NO: 1-20 of WO1998011244).

In some embodiments, the AAV serotype may be, or have, a mutation in the AAV2 sequence to generate AAV2G9 as described in International Publication No. WO2014144229 and herein incorporated by reference in its entirety.

In some embodiments, the AAV serotype may be, or have, a sequence as described in International Publication No. WO2005033321, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to AAV3-3 (SEQ ID NO: 217 of WO2005033321), AAV1 (SEQ ID NO: 219 and 202 of WO2005033321), AAV106.1/hu.37 (SEQ ID No: 10 of WO2005033321), AAV114.3/hu.40 (SEQ ID No: 11 of WO2005033321), AAV127.2/hu.41 (SEQ ID NO:6 and 8 of WO2005033321), AAV128.3/hu.44 (SEQ ID No: 81 of WO2005033321), AAV130.4/hu.48 (SEQ ID NO: 78 of WO2005033321), AAV145.1/hu.53 (SEQ ID No: 176 and 177 of WO2005033321), AAV145.6/hu.56 (SEQ ID NO: 168 and 192 of WO2005033321), AAV16.12/hu.11 (SEQ ID NO: 153 and 57 of WO2005033321), AAV16.8/hu.10 (SEQ ID NO: 156 and 56 of WO2005033321), AAV161.10/hu.60 (SEQ ID No: 170 of WO2005033321), AAV161.6/hu.61 (SEQ ID No: 174 of WO2005033321), AAV1-7/rh.48 (SEQ ID NO: 32 of WO2005033321), AAV1-8/rh.49 (SEQ ID NOs: 103 and 25 of WO2005033321), AAV2 (SEQ ID NO: 211 and 221 of WO2005033321), AAV2-15/rh.62 (SEQ ID No: 33 and 114 of WO2005033321), AAV2-3/rh.61 (SEQ ID NO: 21 of WO2005033321), AAV2-4/rh.50 (SEQ ID No: 23 and 108 of WO2005033321), AAV2-5/rh.51 (SEQ ID NO: 104 and 22 of WO2005033321), AAV3.1/hu.6 (SEQ ID NO: 5 and 84 of WO2005033321), AAV3.1/hu.9 (SEQ ID NO: 155 and 58 of WO2005033321), AAV3-11/rh.53 (SEQ ID NO: 186 and 176 of WO2005033321), AAV3-3 (SEQ ID NO: 200 of WO2005033321), AAV33.12/hu.17 (SEQ ID NO:4 of WO2005033321), AAV33.4/hu.15 (SEQ ID No: 50 of WO2005033321), AAV33.8/hu.16 (SEQ ID No: 51 of WO2005033321), AAV3-9/rh.52 (SEQ ID NO: 96 and 18 of WO2005033321), AAV4-19/rh.55 (SEQ ID NO: 117 of WO2005033321), AAV4-4 (SEQ ID NO: 201 and 218 of WO2005033321), AAV4-9/rh.54 (SEQ ID NO: 116 of WO2005033321), AAV5 (SEQ ID NO: 199 and 216 of WO2005033321), AAV52.1/hu.20 (SEQ ID NO: 63 of WO2005033321), AAV52/hu.19 (SEQ ID NO: 133 of WO2005033321), AAVS-22/rh.58 (SEQ ID No: 27 of WO2005033321), AAV5-3/rh.57 (SEQ ID NO: 105 of WO2005033321), AAV5-3/rh.57 (SEQ ID No: 26 of WO2005033321), AAV58.2/hu.25 (SEQ ID No: 49 of WO2005033321), AAV6 (SEQ ID NO: 203 and 220 of WO2005033321), AAV7 (SEQ ID NO: 222 and 213 of WO2005033321), AAV7.3/hu.7 (SEQ ID No: 55 of WO2005033321), AAV8 (SEQ ID NO: 223 and 214 of WO2005033321), AAVH-1/hu.1 (SEQ ID No: 46 of WO2005033321), AAVH-5/hu.3 (SEQ ID No: 44 of WO2005033321), AAVhu.1 (SEQ ID NO: 144 of WO2005033321), AAVhu.10 (SEQ ID NO: 156 of WO2005033321), AAVhu.11 (SEQ ID NO: 153 of WO2005033321), AAVhu.12 (WO2005033321 SEQ ID NO: 59), AAVhu.13 (SEQ ID NO: 129 of WO2005033321), AAVhu.14/AAV9 (SEQ ID NO: 123 and 3 of WO2005033321), AAVhu.15 (SEQ ID NO: 147 of WO2005033321), AAVhu.16 (SEQ ID NO: 148 of WO2005033321), AAVhu.17 (SEQ ID NO: 83 of WO2005033321), AAVhu.18 (SEQ ID NO: 149 of WO2005033321), AAVhu.19 (SEQ ID NO: 133 of WO2005033321), AAVhu.2 (SEQ ID NO: 143 of WO2005033321), AAVhu.20 (SEQ ID NO: 134 of WO2005033321), AAVhu.21 (SEQ ID NO: 135 of WO2005033321), AAVhu.22 (SEQ ID NO: 138 of WO2005033321), AAVhu.23.2 (SEQ ID NO: 137 of WO2005033321), AAVhu.24 (SEQ ID NO: 136 of WO2005033321), AAVhu.25 (SEQ ID NO: 146 of WO2005033321), AAVhu.27 (SEQ ID NO: 140 of WO2005033321), AAVhu.29 (SEQ ID NO: 132 of WO2005033321), AAVhu.3 (SEQ ID NO: 145 of WO2005033321), AAVhu.31 (SEQ ID NO: 121 of WO2005033321), AAVhu.32 (SEQ ID NO: 122 of WO2005033321), AAVhu.34 (SEQ ID NO: 125 of WO2005033321), AAVhu.35 (SEQ ID NO: 164 of WO2005033321), AAVhu.37 (SEQ ID NO: 88 of WO2005033321), AAVhu.39 (SEQ ID NO: 102 of WO2005033321), AAVhu.4 (SEQ ID NO: 141 of WO2005033321), AAVhu.40 (SEQ ID NO: 87 of WO2005033321), AAVhu.41 (SEQ ID NO: 91 of WO2005033321), AAVhu.42 (SEQ ID NO: 85 of WO2005033321), AAVhu.43 (SEQ ID NO: 160 of WO2005033321), AAVhu.44 (SEQ ID NO: 144 of WO2005033321), AAVhu.45 (SEQ ID NO: 127 of WO2005033321), AAVhu.46 (SEQ ID NO: 159 of WO2005033321), AAVhu.47 (SEQ ID NO: 128 of WO2005033321), AAVhu.48 (SEQ ID NO: 157 of WO2005033321), AAVhu.49 (SEQ ID NO: 189 of WO2005033321), AAVhu.5 (SEQ ID NO: 190 of WO2005033321), AAVhu.52 (SEQ ID NO: 191 of WO2005033321), AAVhu.53 (SEQ ID NO: 186 of WO2005033321), AAVhu.54 (SEQ ID NO: 188 of WO2005033321), AAVhu.55 (SEQ ID NO: 187 of WO2005033321), AAVhu.56 (SEQ ID NO: 192 of WO2005033321), AAVhu.57 (SEQ ID NO: 193 of WO2005033321), AAVhu.58 (SEQ ID NO: 194 of WO2005033321), AAVhu.6 (SEQ ID NO: 84 of WO2005033321), AAVhu.60 (SEQ ID NO: 184 of WO2005033321), AAVhu.61 (SEQ ID NO: 185 of WO2005033321), AAVhu.63 (SEQ ID NO: 195 of WO2005033321), AAVhu.64 (SEQ ID NO: 196 of WO2005033321), AAVhu.66 (SEQ ID NO: 197 of WO2005033321), AAVhu.67 (SEQ ID NO: 198 of WO2005033321), AAVhu.7 (SEQ ID NO: 150 of WO2005033321), AAVhu.8 (WO2005033321 SEQ ID NO: 12), AAVhu.9 (SEQ ID NO: 155 of WO2005033321), AAVLG-10/rh.40 (SEQ ID No: 14 of WO2005033321), AAVLG-4/rh.38 (SEQ ID NO: 86 of WO2005033321), AAVLG-4/rh.38 (SEQ ID No: 7 of WO2005033321), AAVN721-8/rh.43 (SEQ ID NO: 163 of WO2005033321), AAVN721-8/rh.43 (SEQ ID No: 43 of WO2005033321), AAVpi.1 (WO2005033321 SEQ ID NO: 28), AAVpi.2 (WO2005033321 SEQ ID NO: 30), AAVpi.3 (WO2005033321 SEQ ID NO: 29), AAVrh.38 (SEQ ID NO: 86 of WO2005033321), AAVrh.40 (SEQ ID NO: 92 of WO2005033321), AAVrh.43 (SEQ ID NO: 163 of WO2005033321), AAVrh.44 (WO2005033321 SEQ ID NO: 34), AAVrh.45 (WO2005033321 SEQ ID NO: 41), AAVrh.47 (WO2005033321 SEQ ID NO: 38), AAVrh.48 (SEQ ID NO: 115 of WO2005033321), AAVrh.49 (SEQ ID NO: 103 of WO2005033321), AAVrh.50 (SEQ ID NO: 108 of WO2005033321), AAVrh.51 (SEQ ID NO: 104 of WO2005033321), AAVrh.52 (SEQ ID NO: 96 of WO2005033321), AAVrh.53 (SEQ ID NO: 97 of WO2005033321), AAVrh.55 (WO2005033321 SEQ ID NO: 37), AAVrh.56 (SEQ ID NO: 152 of WO2005033321), AAVrh.57 (SEQ ID NO: 105 of WO2005033321), AAVrh.58 (SEQ ID NO: 106 of WO2005033321), AAVrh.59 (WO2005033321 SEQ ID NO: 42), AAVrh.60 (WO2005033321 SEQ ID NO: 31), AAVrh.61 (SEQ ID NO: 107 of WO2005033321), AAVrh.62 (SEQ ID NO: 114 of WO2005033321), AAVrh.64 (SEQ ID NO: 99 of WO2005033321), AAVrh.65 (WO2005033321 SEQ ID NO: 35), AAVrh.68 (WO2005033321 SEQ ID NO: 16), AAVrh.69 (WO2005033321 SEQ ID NO: 39), AAVrh.70 (WO2005033321 SEQ ID NO: 20), AAVrh.72 (WO2005033321 SEQ ID NO: 9), or variants thereof including, but not limited to, AAVcy.2, AAVcy.3, AAVcy.4, AAVcy.5, AAVcy.6, AAVrh.12, AAVrh.17, AAVrh.18, AAVrh.19, AAVrh.21, AAVrh.22, AAVrh.23, AAVrh.24, AAVrh.25, AAVrh.25/42 15, AAVrh.31, AAVrh.32, AAVrh.33, AAVrh.34, AAVrh.35, AAVrh.36, AAVrh.37, AAVrh14. Non limiting examples of variants include SEQ ID NO: 13, 15, 17, 19, 24, 36, 40, 45, 47, 48, 51-54, 60-62, 64-77, 79, 80, 82, 89, 90, 93-95, 98, 100, 101, 109-113, 118-120, 124, 126, 131, 139, 142, 151,154, 158, 161, 162, 165-183, 202, 204-212, 215, 219, 224-236, of WO2005033321, the contents of which are herein incorporated by reference in their entirety.

In some embodiments, the AAV serotype may be, or have, a sequence as described in International Publication No. WO2015168666, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAVrh8R (SEQ ID NO: 9 of WO2015168666), AAVrh8R A586R mutant (SEQ ID NO: 10 of WO2015168666), AAVrh8R R533A mutant (SEQ ID NO: 11 of WO2015168666), or variants thereof.

In some embodiments, the AAV serotype may be, or have, a sequence as described in U.S. Pat. No. 9,233,131, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAVhE1.1 (SEQ ID NO:44 of U.S. Pat. No. 9,233,131), AAVhEr1.5 (SEQ ID NO:45 of U.S. Pat. No. 9,233,131), AAVhER1.14 (SEQ ID NO:46 of U.S. Pat. No. 9,233,131), AAVhEr1.8 (SEQ ID NO:47 of U.S. Pat. No. 9,233,131), AAVhEr1.16 (SEQ ID NO:48 of U.S. Pat. No. 9,233,131), AAVhEr1.18 (SEQ ID NO:49 of U.S. Pat. No. 9,233,131), AAVhEr1.35 (SEQ ID NO:50 of U.S. Pat. No. 9,233,131), AAVhEr1.7 (SEQ ID NO:51 of U.S. Pat. No. 9,233,131), AAVhEr1.36 (SEQ ID NO:52 of U.S. Pat. No. 9,233,131), AAVhEr2.29 (SEQ ID NO:53 of U.S. Pat. No. 9,233,131), AAVhEr2.4 (SEQ ID NO:54 of U.S. Pat. No. 9,233,131), AAVhEr2.16 (SEQ ID NO:55 of U.S. Pat. No. 9,233,131), AAVhEr2.30 (SEQ ID NO:56 of U.S. Pat. No. 9,233,131), AAVhEr2.31 (SEQ ID NO:58 of U.S. Pat. No. 9,233,131), AAVhEr2.36 (SEQ ID NO:57 of U.S. Pat. No. 9,233,131), AAVhER1.23 (SEQ ID NO:53 of U.S. Pat. No. 9,233,131), AAVhEr3.1 (SEQ ID NO:59 of U.S. Pat. No. 9,233,131), AAV2.5T (SEQ ID NO:42 of U.S. Pat. No. 9,233,131), or variants thereof.

In some embodiments, the AAV serotype may be, or have, a sequence as described in United States Patent Publication No. US20150376607, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV-PAEC (SEQ ID NO:1 of US20150376607), AAV-LK01 (SEQ ID NO:2 of US20150376607), AAV-LK02 (SEQ ID NO:3 of US20150376607), AAV-LK03 (SEQ ID NO:4 of US20150376607), AAV-LK04 (SEQ ID NO:5 of US20150376607), AAV-LK05 (SEQ ID NO:6 of US20150376607), AAV-LK06 (SEQ ID NO:7 of US20150376607), AAV-LK07 (SEQ ID NO:8 of US20150376607), AAV-LK08 (SEQ ID NO:9 of US20150376607), AAV-LK09 (SEQ ID NO:10 of US20150376607), AAV-LK10 (SEQ ID NO:11 of US20150376607), AAV-LK11 (SEQ ID NO:12 of US20150376607), AAV-LK12 (SEQ ID NO:13 of US20150376607), AAV-LK13 (SEQ ID NO:14 of US20150376607), AAV-LK14 (SEQ ID NO:15 of US20150376607), AAV-LK15 (SEQ ID NO:16 of US20150376607), AAV-LK16 (SEQ ID NO:17 of US20150376607), AAV-LK17 (SEQ ID NO:18 of US20150376607), AAV-LK18 (SEQ ID NO:19 of US20150376607), AAV-LK19 (SEQ ID NO:20 of US20150376607), AAV-PAEC2 (SEQ ID NO:21 of US20150376607), AAV-PAEC4 (SEQ ID NO:22 of US20150376607), AAV-PAEC6 (SEQ ID NO:23 of US20150376607), AAV-PAEC7 (SEQ ID NO:24 of US20150376607), AAV-PAEC8 (SEQ ID NO:25 of US20150376607), AAV-PAEC11 (SEQ ID NO:26 of US20150376607), AAV-PAEC12 (SEQ ID NO:27, of US20150376607), or variants thereof.

In some embodiments, the AAV serotype may be, or have, a sequence as described in U.S. Pat. No. 9,163,261, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV-2-pre-miRNA-101 (SEQ ID NO: 1 U.S. Pat. No. 9,163,261), or variants thereof.

In some embodiments, the AAV serotype may be, or have, a sequence as described in United States Patent Publication No. US20150376240, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV-8h (SEQ ID NO: 6 of US20150376240), AAV-8b (SEQ ID NO: 5 of US20150376240), AAV-h (SEQ ID NO: 2 of US20150376240), AAV-b (SEQ ID NO: 1 of US20150376240), or variants thereof.

In some embodiments, the AAV serotype may be, or have, a sequence as described in United States Patent Publication No. US20160017295, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV SM 10-2 (SEQ ID NO: 22 of US20160017295), AAV Shuffle 100-1 (SEQ ID NO: 23 of US20160017295), AAV Shuffle 100-3 (SEQ ID NO: 24 of US20160017295), AAV Shuffle 100-7 (SEQ ID NO: 25 of US20160017295), AAV Shuffle 10-2 (SEQ ID NO: 34 of US20160017295), AAV Shuffle 10-6 (SEQ ID NO: 35 of US20160017295), AAV Shuffle 10-8 (SEQ ID NO: 36 of US20160017295), AAV Shuffle 100-2 (SEQ ID NO: 37 of US20160017295), AAV SM 10-1 (SEQ ID NO: 38 of US20160017295), AAV SM 10-8 (SEQ ID NO: 39 of US20160017295), AAV SM 100-3 (SEQ ID NO: 40 of US20160017295), AAV SM 100-10 (SEQ ID NO: 41 of US20160017295), or variants thereof.

In some embodiments, the AAV serotype may be, or have, a sequence as described in United States Patent Publication No. US20150238550, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, BNP61 AAV (SEQ ID NO: 1 of US20150238550), BNP62 AAV (SEQ ID NO: 3 of US20150238550), BNP63 AAV (SEQ ID NO: 4 of US20150238550), or variants thereof.

In some embodiments, the AAV serotype may be or may have a sequence as described in United States Patent Publication No. US20150315612, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAVrh.50 (SEQ ID NO: 108 of US20150315612), AAVrh.43 (SEQ ID NO: 163 of US20150315612), AAVrh.62 (SEQ ID NO: 114 of US20150315612), AAVrh.48 (SEQ ID NO: 115 of US20150315612), AAVhu.19 (SEQ ID NO: 133 of US20150315612), AAVhu.11 (SEQ ID NO: 153 of US20150315612), AAVhu.53 (SEQ ID NO: 186 of US20150315612), AAV4-8/rh.64 (SEQ ID No: 15 of US20150315612), AAVLG-9/hu.39 (SEQ ID No: 24 of US20150315612), AAV54.5/hu.23 (SEQ ID No: 60 of US20150315612), AAV54.2/hu.22 (SEQ ID No: 67 of US20150315612), AAV54.7/hu.24 (SEQ ID No: 66 of US20150315612), AAV54.1/hu.21 (SEQ ID No: 65 of US20150315612), AAV54.4R/hu.27 (SEQ ID No: 64 of US20150315612), AAV46.2/hu.28 (SEQ ID No: 68 of US20150315612), AAV46.6/hu.29 (SEQ ID No: 69 of US20150315612), AAV128.1/hu.43 (SEQ ID No: 80 of US20150315612), or variants thereof.

In some embodiments, the AAV serotype may be, or have, a sequence as described in International Publication No. WO2015121501, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, true type AAV (ttAAV) (SEQ ID NO: 2 of WO2015121501), “UPenn AAV10” (SEQ ID NO: 8 of WO2015121501), “Japanese AAV10” (SEQ ID NO: 9 of WO2015121501), or variants thereof.

According to the present disclosure, AAV capsid serotype selection or use may be from a variety of species. In some embodiments, the AAV may be an avian AAV (AAAV). The AAAV serotype may be, or have, a sequence as described in U.S. Pat. No. 9,238,800, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAAV (SEQ ID NO: 1, 2, 4, 6, 8, 10, 12, and 14 of U.S. Pat. No. 9,238,800), or variants thereof.

In some embodiments, the AAV may be a bovine AAV (BAAV). The BAAV serotype may be, or have, a sequence as described in U.S. Pat. No. 9,193,769, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, BAAV (SEQ ID NO: 1 and 6 of U.S. Pat. No. 9,193,769), or variants thereof. The BAAV serotype may be or have a sequence as described in U.S. Pat. No. 7,427,396, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, BAAV (SEQ ID NO: 5 and 6 of U.S. Pat. No. 7,427,396), or variants thereof.

In some embodiments, the AAV may be a caprine AAV. The caprine AAV serotype may be, or have, a sequence as described in U.S. Pat. No. 7,427,396, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, caprine AAV (SEQ ID NO: 3 of U.S. Pat. No. 7,427,396), or variants thereof.

In other embodiments the AAV may be engineered as a hybrid AAV from two or more parental serotypes. In some embodiments, the AAV may be AAV2G9 which comprises sequences from AAV2 and AAV9. The AAV2G9 AAV serotype may be, or have, a sequence as described in United States Patent Publication No. US20160017005, the contents of which are herein incorporated by reference in its entirety.

In some embodiments, the AAV may be a serotype generated by the AAV9 capsid library with mutations in amino acids 390-627 (VP1 numbering) as described by Pulicherla et al. (Molecular Therapy 19(6):1070-1078 (2011), the contents of which are herein incorporated by reference in their entirety. The serotype and corresponding nucleotide and amino acid substitutions may be, but is not limited to, AAV9.1 (G1594C; D532H), AAV6.2 (T1418A and T1436X; V473D and 1479K), AAV9.3 (T1238A; F413Y), AAV9.4 (T1250C and A1617T; F417S), AAV9.5 (A1235G, A1314T, A1642G, C1760T; Q412R, T548A, A587V), AAV9.6 (T1231A; F4111), AAV9.9 (G1203A. G1785T; W595C), AAV9.10 (A1500G, T1676C; M559T), AAV9.11 (A1425T, A1702C, A1769T; T568P, Q590L), AAV9.13 (A1369C, A1720T; N457H, T574S), AAV9.14 (T1340A, T1362C, T1560C, G1713A; L447H), AAV9.16 (A1775T; Q592L), AAV9.24 (T1507C, T1521G; W503R), AAV9.26 (A1337G, A1769C; Y446C, Q590P), AAV9.33 (A1667C; D556A), AAV9.34 (A1534G, C1794T; N512D), AAV9.35 (A1289T, T1450A, C1494T, A1515T, C1794A, G1816A; Q430L, Y484N, N98K, V6061), AAV9.40 (A1694T, E565V), AAV9.41 (A1348T, T1362C; T450S), AAV9.44 (A1684C, A1701T, A1737G; N562H, K567N), AAV9.45 (A1492T, C1804T; N498Y, L602F), AAV9.46 (G1441C, T1525C, T1549G; G481R, W509R, L517V), 9.47 (G1241A, G1358A, A1669G, C1745T; S414N, G453D, K557E, T5821), AAV9.48 (C1445T, A1736T; P482L, Q579L), AAV9.50 (A1638T, C1683T, T1805A; Q546H, L602H), AAV9.53 (G1301A, A1405C, C1664T, G1811T; R134Q, S469R, A555V, G604V), AAV9.54 (C1531A, T1609A; L5111, L537M), AAV9.55 (T1605A; F535L), AAV9.58 (C1475T, C1579A; T4921, H527N), AAV.59 (T1336C; Y446H), AAV9.61 (A1493T; N4981), AAV9.64 (C1531A, A1617T; L5111), AAV9.65 (C1335T, T1530C, C1568A; A523D), AAV9.68 (C1510A; P504T), AAV9.80 (G1441A, G481R), AAV9.83 (C1402A. A1500T; P468T, E500D), AAV9.87 (T1464C, T1468C; S490P), AAV9.90 (A1196T; Y399F), AAV9.91 (T1316G, A1583T, C1782G, T1806C; L439R, K5281), AAV9.93 (A1273G, A1421G, A1638C, C1712T, G1732A, A1744T, A1832T; S425G, Q474R, Q546H, P571L, G578R, T582S, D611V), AAV9.94 (A1675T; M559L) and AAV9.95 (T1605A; F535L).

In some embodiments, the AAV serotype may be, or have, a sequence as described in International Publication No. WO2016049230, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to AAVF1/HSC1 (SEQ ID NO; 2 and 20 of WO2016049230), AAVF2/HSC2 (SEQ ID NO; 3 and 21 of WO2016049230), AAVF3/HSC3 (SEQ ID NO; 5 and 22 of WO2016049230), AAVF4/HSC4 (SEQ ID NO; 6 and 23 of WO2016049230), AAVF5/HSC5 (SEQ ID NO; 11 and 25 of WO2016049230), AAVF6/HSC6 (SEQ ID NO; 7 and 24 of WO2016049230), AAVF7/HSC7 (SEQ ID NO; 8 and 27 of WO2016049230), AAVF8/HSC8 (SEQ ID NO: 9 and 28 of WO2016049230), AAVF9/HSC9 (SEQ ID NO: 10 and 29 of WO2016049230), AAVF11/HSC11 (SEQ ID NO: 4 and 26 of WO2016049230), AAVF12/HSC12 (SEQ ID NO: 12 and 30 of WO2016049230), AAVF13/HSC13 (SEQ ID NO: 14 and 31 of WO2016049230), AAVF14/HSC14 (SEQ ID NO: 15 and 32 of WO2016049230), AAVF15/HSC15 (SEQ ID NO: 16 and 33 of WO2016049230), AAVF16/HSC16 (SEQ ID NO: 17 and 34 of WO2016049230), AAVF17/HSC17 (SEQ ID NO: 13 and 35 of WO2016049230), or variants or derivatives thereof.

In some embodiments, the AAV serotype may be, or have, a sequence as described in U.S. Pat. No. 8,734,809, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV CBr-E1 (SEQ ID NO: 13 and 87 of U.S. Pat. No. 8,734,809), AAV CBr-E2 (SEQ ID NO: 14 and 88 of U.S. Pat. No. 8,734,809), AAV CBr-E3 (SEQ ID NO: 15 and 89 of U.S. Pat. No. 8,734,809), AAV CBr-E4 (SEQ ID NO: 16 and 90 of U.S. Pat. No. 8,734,809), AAV CBr-E5 (SEQ ID NO: 17 and 91 of U.S. Pat. No. 8,734,809), AAV CBr-e5 (SEQ ID NO: 18 and 92 of U.S. Pat. No. 8,734,809), AAV CBr-E6 (SEQ ID NO: 19 and 93 of U.S. Pat. No. 8,734,809), AAV CBr-E7 (SEQ ID NO: 20 and 94 of U.S. Pat. No. 8,734,809), AAV CBr-E8 (SEQ ID NO: 21 and 95 of U.S. Pat. No. 8,734,809), AAV CLv-D1 (SEQ ID NO: 22 and 96 of U.S. Pat. No. 8,734,809), AAV CLv-D2 (SEQ ID NO: 23 and 97 of U.S. Pat. No. 8,734,809), AAV CLv-D3 (SEQ ID NO: 24 and 98 of U.S. Pat. No. 8,734,809), AAV CLv-D4 (SEQ ID NO: 25 and 99 of U.S. Pat. No. 8,734,809), AAV CLv-D5 (SEQ ID NO: 26 and 100 of U.S. Pat. No. 8,734,809), AAV CLv-D6 (SEQ ID NO: 27 and 101 of U.S. Pat. No. 8,734,809), AAV CLv-D7 (SEQ ID NO: 28 and 102 of U.S. Pat. No. 8,734,809), AAV CLv-D8 (SEQ ID NO: 29 and 103 of U.S. Pat. No. 8,734,809), AAV CLv-E1 (SEQ ID NO: 13 and 87 of U.S. Pat. No. 8,734,809), AAV CLv-R1 (SEQ ID NO: 30 and 104 of U.S. Pat. No. 8,734,809), AAV CLv-R2 (SEQ ID NO: 31 and 105 of U.S. Pat. No. 8,734,809), AAV CLv-R3 (SEQ ID NO: 32 and 106 of U.S. Pat. No. 8,734,809), AAV CLv-R4 (SEQ ID NO: 33 and 107 of U.S. Pat. No. 8,734,809), AAV CLv-R5 (SEQ ID NO: 34 and 108 of U.S. Pat. No. 8,734,809), AAV CLv-R6 (SEQ ID NO: 35 and 109 of U.S. Pat. No. 8,734,809), AAV CLv-R7 (SEQ ID NO: 36 and 110 of U.S. Pat. No. 8,734,809), AAV CLv-R8 (SEQ ID NO: X and X of U.S. Pat. No. 8,734,809), AAV CLv-R9 (SEQ ID NO: X and X of U.S. Pat. No. 8,734,809), AAV CLg-F1 (SEQ ID NO: 39 and 113 of U.S. Pat. No. 8,734,809), AAV CLg-F2 (SEQ ID NO: 40 and 114 of U.S. Pat. No. 8,734,809), AAV CLg-F3 (SEQ ID NO: 41 and 115 of U.S. Pat. No. 8,734,809), AAV CLg-F4 (SEQ ID NO: 42 and 116 of U.S. Pat. No. 8,734,809), AAV CLg-F5 (SEQ ID NO: 43 and 117 of U.S. Pat. No. 8,734,809), AAV CLg-F6 (SEQ ID NO: 43 and 117 of U.S. Pat. No. 8,734,809), AAV CLg-F7 (SEQ ID NO: 44 and 118 of U.S. Pat. No. 8,734,809), AAV CLg-F8 (SEQ ID NO: 43 and 117 of U.S. Pat. No. 8,734,809), AAV CSp-1 (SEQ ID NO: 45 and 119 of U.S. Pat. No. 8,734,809), AAV CSp-10 (SEQ ID NO: 46 and 120 of U.S. Pat. No. 8,734,809), AAV CSp-11 (SEQ ID NO: 47 and 121 of U.S. Pat. No. 8,734,809), AAV CSp-2 (SEQ ID NO: 48 and 122 of U.S. Pat. No. 8,734,809), AAV CSp-3 (SEQ ID NO: 49 and 123 of U.S. Pat. No. 8,734,809), AAV CSp-4 (SEQ ID NO: 50 and 124 of U.S. Pat. No. 8,734,809), AAV CSp-6 (SEQ ID NO: 51 and 125 of U.S. Pat. No. 8,734,809), AAV CSp-7 (SEQ ID NO: 52 and 126 of U.S. Pat. No. 8,734,809), AAV CSp-8 (SEQ ID NO: 53 and 127 of U.S. Pat. No. 8,734,809), AAV CSp-9 (SEQ ID NO: 54 and 128 of U.S. Pat. No. 8,734,809), AAV CHt-2 (SEQ ID NO: 55 and 129 of U.S. Pat. No. 8,734,809), AAV CHt-3 (SEQ ID NO: 56 and 130 of U.S. Pat. No. 8,734,809), AAV CKd-1 (SEQ ID NO: 57 and 131 of U.S. Pat. No. 8,734,809), AAV CKd-10 (SEQ ID NO: 58 and 132 of U.S. Pat. No. 8,734,809), AAV CKd-2 (SEQ ID NO: 59 and 133 of U.S. Pat. No. 8,734,809), AAV CKd-3 (SEQ ID NO: 60 and 134 of U.S. Pat. No. 8,734,809), AAV CKd-4 (SEQ ID NO: 61 and 135 of U.S. Pat. No. 8,734,809), AAV CKd-6 (SEQ ID NO: 62 and 136 of U.S. Pat. No. 8,734,809), AAV CKd-7 (SEQ ID NO: 63 and 137 of U.S. Pat. No. 8,734,809), AAV CKd-8 (SEQ ID NO: 64 and 138 of U.S. Pat. No. 8,734,809), AAV CLv-1 (SEQ ID NO: 35 and 139 of U.S. Pat. No. 8,734,809), AAV CLv-12 (SEQ ID NO: 66 and 140 of U.S. Pat. No. 8,734,809), AAV CLv-13 (SEQ ID NO: 67 and 141 of U.S. Pat. No. 8,734,809), AAV CLv-2 (SEQ ID NO: 68 and 142 of U.S. Pat. No. 8,734,809), AAV CLv-3 (SEQ ID NO: 69 and 143 of U.S. Pat. No. 8,734,809), AAV CLv-4 (SEQ ID NO: 70 and 144 of U.S. Pat. No. 8,734,809), AAV CLv-6 (SEQ ID NO: 71 and 145 of U.S. Pat. No. 8,734,809), AAV CLv-8 (SEQ ID NO: 72 and 146 of U.S. Pat. No. 8,734,809), AAV CKd-B1 (SEQ ID NO: 73 and 147 of U.S. Pat. No. 8,734,809), AAV CKd-B2 (SEQ ID NO: 74 and 148 of U.S. Pat. No. 8,734,809), AAV CKd-B3 (SEQ ID NO: 75 and 149 of U.S. Pat. No. 8,734,809), AAV CKd-B4 (SEQ ID NO: 76 and 150 of U.S. Pat. No. 8,734,809), AAV CKd-B5 (SEQ ID NO: 77 and 151 of U.S. Pat. No. 8,734,809), AAV CKd-B6 (SEQ ID NO: 78 and 152 of U.S. Pat. No. 8,734,809), AAV CKd-B7 (SEQ ID NO: 79 and 153 of U.S. Pat. No. 8,734,809), AAV CKd-B8 (SEQ ID NO: 80 and 154 of U.S. Pat. No. 8,734,809), AAV CKd-H1 (SEQ ID NO: 81 and 155 of U.S. Pat. No. 8,734,809), AAV CKd-H2 (SEQ ID NO: 82 and 156 of U.S. Pat. No. 8,734,809), AAV CKd-H3 (SEQ ID NO: 83 and 157 of U.S. Pat. No. 8,734,809), AAV CKd-H4 (SEQ ID NO: 84 and 158 of U.S. Pat. No. 8,734,809), AAV CKd-H5 (SEQ ID NO: 85 and 159 of U.S. Pat. No. 8,734,809), AAV CKd-H6 (SEQ ID NO: 77 and 151 of U.S. Pat. No. 8,734,809), AAV CHt-1 (SEQ ID NO: 86 and 160 of U.S. Pat. No. 8,734,809), AAV CLv1-1 (SEQ ID NO: 171 of U.S. Pat. No. 8,734,809), AAV CLv1-2 (SEQ ID NO: 172 of U.S. Pat. No. 8,734,809), AAV CLv1-3 (SEQ ID NO: 173 of U.S. Pat. No. 8,734,809), AAV CLv1-4 (SEQ ID NO: 174 of U.S. Pat. No. 8,734,809), AAV Clv1-7 (SEQ ID NO: 175 of U.S. Pat. No. 8,734,809), AAV Clv1-8 (SEQ ID NO: 176 of U.S. Pat. No. 8,734,809), AAV Clv1-9 (SEQ ID NO: 177 of U.S. Pat. No. 8,734,809), AAV Clv1-10 (SEQ ID NO: 178 of U.S. Pat. No. 8,734,809), AAV.VR-355 (SEQ ID NO: 181 of U.S. Pat. No. 8,734,809), AAV.hu.48R3 (SEQ ID NO: 183 of U.S. Pat. No. 8,734,809), or variants or derivatives thereof.

In some embodiments, the AAV serotype may be, or have, a sequence as described in International Publication No. WO2016065001, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to AAV CHt-P2 (SEQ ID NO: 1 and 51 of WO2016065001), AAV CHt-P5 (SEQ ID NO: 2 and 52 of WO2016065001), AAV CHt-P9 (SEQ ID NO: 3 and 53 of WO2016065001), AAV CBr-7.1 (SEQ ID NO: 4 and 54 of WO2016065001), AAV CBr-7.2 (SEQ ID NO: 5 and 55 of WO2016065001), AAV CBr-7.3 (SEQ ID NO: 6 and 56 of WO2016065001), AAV CBr-7.4 (SEQ ID NO: 7 and 57 of WO2016065001), AAV CBr-7.5 (SEQ ID NO: 8 and 58 of WO2016065001), AAV CBr-7.7 (SEQ ID NO: 9 and 59 of WO2016065001), AAV CBr-7.8 (SEQ ID NO: 10 and 60 of WO2016065001), AAV CBr-7.10 (SEQ ID NO: 11 and 61 of WO2016065001), AAV CKd-N3 (SEQ ID NO: 12 and 62 of WO2016065001), AAV CKd-N4 (SEQ ID NO: 13 and 63 of WO2016065001), AAV CKd-N9 (SEQ ID NO: 14 and 64 of WO2016065001), AAV CLv-L4 (SEQ ID NO: 15 and 65 of WO2016065001), AAV CLv-L5 (SEQ ID NO: 16 and 66 of WO2016065001), AAV CLv-L6 (SEQ ID NO: 17 and 67 of WO2016065001), AAV CLv-K1 (SEQ ID NO: 18 and 68 of WO2016065001), AAV CLv-K3 (SEQ ID NO: 19 and 69 of WO2016065001), AAV CLv-K6 (SEQ ID NO: 20 and 70 of WO2016065001), AAV CLv-M1 (SEQ ID NO: 21 and 71 of WO2016065001), AAV CLv-M11 (SEQ ID NO: 22 and 72 of WO2016065001), AAV CLv-M2 (SEQ ID NO: 23 and 73 of WO2016065001), AAV CLv-M5 (SEQ ID NO: 24 and 74 of WO2016065001), AAV CLv-M6 (SEQ ID NO: 25 and 75 of WO2016065001), AAV CLv-M7 (SEQ ID NO: 26 and 76 of WO2016065001), AAV CLv-M8 (SEQ ID NO: 27 and 77 of WO2016065001), AAV CLv-M9 (SEQ ID NO: 28 and 78 of WO2016065001), AAV CHt-P1 (SEQ ID NO: 29 and 79 of WO2016065001), AAV CHt-P6 (SEQ ID NO: 30 and 80 of WO2016065001), AAV CHt-P8 (SEQ ID NO: 31 and 81 of WO2016065001), AAV CHt-6.1 (SEQ ID NO: 32 and 82 of WO2016065001), AAV CHt-6.10 (SEQ ID NO: 33 and 83 of WO2016065001), AAV CHt-6.5 (SEQ ID NO: 34 and 84 of WO2016065001), AAV CHt-6.6 (SEQ ID NO: 35 and 85 of WO2016065001), AAV CHt-6.7 (SEQ ID NO: 36 and 86 of WO2016065001), AAV CHt-6.8 (SEQ ID NO: 37 and 87 of WO2016065001), AAV CSp-8.10 (SEQ ID NO: 38 and 88 of WO2016065001), AAV CSp-8.2 (SEQ ID NO: 39 and 89 of WO2016065001), AAV CSp-8.4 (SEQ ID NO: 40 and 90 of WO2016065001), AAV CSp-8.5 (SEQ ID NO: 41 and 91 of WO2016065001), AAV CSp-8.6 (SEQ ID NO: 42 and 92 of WO2016065001), AAV CSp-8.7 (SEQ ID NO: 43 and 93 of WO2016065001), AAV CSp-8.8 (SEQ ID NO: 44 and 94 of WO2016065001), AAV CSp-8.9 (SEQ ID NO: 45 and 95 of WO2016065001), AAV CBr-B7.3 (SEQ ID NO: 46 and 96 of WO2016065001), AAV CBr-B7.4 (SEQ ID NO: 47 and 97 of WO2016065001), AAV3B (SEQ ID NO: 48 and 98 of WO2016065001), AAV4 (SEQ ID NO: 49 and 99 of WO2016065001), AAV5 (SEQ ID NO: 50 and 100 of WO2016065001), or variants or derivatives thereof.

In some embodiments, the AAV particle may have, or may be a serotype selected from any of those found in Table 1.

In some embodiments, the AAV capsid may comprise a sequence, fragment or variant thereof, of any of the sequences in Table 1.

In some embodiments, the AAV capsid may be encoded by a sequence, fragment or variant as described in Table 1.

In any of the DNA and RNA sequences referenced and/or described herein, the single letter symbol has the following description: A for adenine; C for cytosine; G for guanine; T for thymine; U for Uracil; W for weak bases such as adenine or thymine; S for strong nucleotides such as cytosine and guanine; M for amino nucleotides such as adenine and cytosine; K for keto nucleotides such as guanine and thymine; R for purines adenine and guanine; Y for pyrimidine cytosine and thymine; B for any base that is not A (e.g., cytosine, guanine, and thymine); D for any base that is not C (e.g., adenine, guanine, and thymine); H for any base that is not G (e.g., adenine, cytosine, and thymine); V for any base that is not T (e.g., adenine, cytosine, and guanine). N for any nucleotide (which is not a gap); and Z is for zero.

In any of the amino acid sequences referenced and/or described herein, the single letter symbol has the following description: G (Gly) for Glycine; A (Ala) for Alanine; L (Leu) for Leucine; M (Met) for Methionine; F (Phe) for Phenylalanine; W (Trp) for Tryptophan; K (Lys) for Lysine; Q (Gin) for Glutamine; E (Glu) for Glutamic Acid; S (Ser) for Serine; P (Pro) for Proline; V (Val) for Valine; I (Ile) for Isoleucine; C (Cys) for Cysteine; Y (Tyr) for Tyrosine; H (His) for Histidine; R (Arg) for Arginine; N (Asn) for Asparagine; D (Asp) for Aspartic Acid; T (Thr) for Threonine; B (Asx) for Aspartic acid or Asparagine; J (Xle) for Leucine or Isoleucine; O (Pyl) for Pyrrolysine. U (Sec) for Selenocysteine, X (Xaa) for any amino acid; and Z (Glx) for Glutamine or Glutamic acid.

TABLE 1 AAV Serotypes SEQ Serotype ID NO: Reference Information VOY101 1 — VOY101 2 — VOY201 3 — VOY201 4534 — PHP.N/PHP.B-DGT 4 WO2017100671 SEQ ID NO: 46 AAVPHP.B or G2B-26 5 WO2015038958 SEQ ID NO: 8 and 13 AAVPHP.B 6 WO2015038958 SEQ ID NO: 9 AAVG2B-13 7 WO2015038958 SEQ ID NO: 12 AAVTH1.1-32 8 WO2015038958 SEQ ID NO: 14 AAVTH1.1-35 9 WO2015038958 SEQ ID NO: 15 PHP.S/G2A12 10 WO2017100671 SEQ ID NO: 47 AAV9/hu.14 K449R 11 WO2017100671 SEQ ID NO: 45 AAV1 12 US20150159173 SEQ ID NO: 11, US20150315612 SEQ ID NO: 202 AAV1 13 US20160017295 SEQ ID NO: 1, US20030138772 SEQ ID NO: 64, US20150159173 SEQ ID NO: 27, US20150315612 SEQ ID NO: 219, U.S. Pat. No. 7,198,951 SEQ ID NO: 5 AAV1 14 US20030138772 SEQ ID NO: 6 AAV1.3 15 US20030138772 SEQ ID NO: 14 AAV10 16 US20030138772 SEQ ID NO: 117 AAV10 17 WO2015121501 SEQ ID NO: 9 AAV10 18 WO2015121501 SEQ ID NO: 8 AAV11 19 US20030138772 SEQ ID NO: 118 AAV12 20 US20030138772 SEQ ID NO: 119 AAV2 21 US20150159173 SEQ ID NO: 7, US20150315612 SEQ ID NO: 211 AAV2 22 US20030138772 SEQ ID NO: 70, US20150159173 SEQ ID NO: 23, US20150315612 SEQ ID NO: 221, US20160017295 SEQ ID NO: 2, U.S. Pat. No. 6,156,303 SEQ ID NO: 4, U.S. Pat. No. 7,198,951 SEQ ID NO: 4, WO2015121501 SEQ ID NO: 1 AAV2 23 U.S. Pat. No. 6,156,303 SEQ ID NO: 8 AAV2 24 US20030138772 SEQ ID NO: 7 AAV2 25 U.S. Pat. No. 6,156,303 SEQ ID NO: 3 AAV2.5T 26 U.S. Pat. No. 9,233,131 SEQ ID NO: 42 AAV223.10 27 US20030138772 SEQ ID NO: 75 AAV223.2 28 US20030138772 SEQ ID NO: 49 AAV223.2 29 US20030138772 SEQ ID NO: 76 AAV223.4 30 US20030138772 SEQ ID NO: 50 AAV223.4 31 US20030138772 SEQ ID NO: 73 AAV223.5 32 US20030138772 SEQ ID NO: 51 AAV223.5 33 US20030138772 SEQ ID NO: 74 AAV223.6 34 US20030138772 SEQ ID NO: 52 AAV223.6 35 US20030138772 SEQ ID NO: 78 AAV223.7 36 US20030138772 SEQ ID NO: 53 AAV223.7 37 US20030138772 SEQ ID NO: 77 AAV29.3 38 US20030138772 SEQ ID NO: 82 AAV29.4 39 US20030138772 SEQ ID NO: 12 AAV29.5 40 US20030138772 SEQ ID NO: 83 AAV29.5 (AAVbb.2) 41 US20030138772 SEQ ID NO: 13 AAV3 42 US20150159173 SEQ ID NO: 12 AAV3 43 US20030138772 SEQ ID NO: 71, US20150159173 SEQ ID NO: 28, US20160017295 SEQ ID NO: 3, U.S. Pat. No. 7,198,951 SEQ ID NO: 6 AAV3 44 US20030138772 SEQ ID NO: 8 AAV3.3b 45 US20030138772 SEQ ID NO: 72 AAV3-3 46 US20150315612 SEQ ID NO: 200 AAV3-3 47 US20150315612 SEQ ID NO: 217 AAV3a 48 U.S. Pat. No. 6,156,303 SEQ ID NO: 5 AAV3a 49 U.S. Pat. No. 6,156,303 SEQ ID NO: 9 AAV3b 50 U.S. Pat. No. 6,156,303 SEQ ID NO: 6 AAV3b 51 U.S. Pat. No. 6,156,303 SEQ ID NO: 10 AAV3b 52 U.S. Pat. No. 6,156,303 SEQ ID NO: 1 AAV4 53 US20140348794 SEQ ID NO: 17 AAV4 54 US20140348794 SEQ ID NO: 5 AAV4 55 US20140348794 SEQ ID NO: 3 AAV4 56 US20140348794 SEQ ID NO: 14 AAV4 57 US20140348794 SEQ ID NO: 15 AAV4 58 US20140348794 SEQ ID NO: 19 AAV4 59 US20140348794 SEQ ID NO: 12 AAV4 60 US20140348794 SEQ ID NO: 13 AAV4 61 US20140348794 SEQ ID NO: 7 AAV4 62 US20140348794 SEQ ID NO: 8 AAV4 63 US20140348794 SEQ ID NO: 9 AAV4 64 US20140348794 SEQ ID NO: 2 AAV4 65 US20140348794 SEQ ID NO: 10 AAV4 66 US20140348794 SEQ ID NO: 11 AAV4 67 US20140348794 SEQ ID NO: 18 AAV4 68 US20030138772 SEQ ID NO: 63, US20160017295 SEQ ID NO: 4, US20140348794 SEQ ID NO: 4 AAV4 69 US20140348794 SEQ ID NO: 16 AAV4 70 US20140348794 SEQ ID NO: 20 AAV4 71 US20140348794 SEQ ID NO: 6 AAV4 72 US20140348794 SEQ ID NO: 1 AAV42.2 73 US20030138772 SEQ ID NO: 9 AAV42.2 74 US20030138772 SEQ ID NO: 102 AAV42.3b 75 US20030138772 SEQ ID NO: 36 AAV42.3B 76 US20030138772 SEQ ID NO: 107 AAV42.4 77 US20030138772 SEQ ID NO: 33 AAV42.4 78 US20030138772 SEQ ID NO: 88 AAV42.8 79 US20030138772 SEQ ID NO: 27 AAV42.8 80 US20030138772 SEQ ID NO: 85 AAV43.1 81 US20030138772 SEQ ID NO: 39 AAV43.1 82 US20030138772 SEQ ID NO: 92 AAV43.12 83 US20030138772 SEQ ID NO: 41 AAV43.12 84 US20030138772 SEQ ID NO: 93 AAV43.20 85 US20030138772 SEQ ID NO: 42 AAV43.20 86 US20030138772 SEQ ID NO: 99 AAV43.21 87 US20030138772 SEQ ID NO: 43 AAV43.21 88 US20030138772 SEQ ID NO: 96 AAV43.23 89 US20030138772 SEQ ID NO: 44 AAV43.23 90 US20030138772 SEQ ID NO: 98 AAV43.25 91 US20030138772 SEQ ID NO: 45 AAV43.25 92 US20030138772 SEQ ID NO: 97 AAV43.5 93 US20030138772 SEQ ID NO: 40 AAV43.5 94 US20030138772 SEQ ID NO: 94 AAV4-4 95 US20150315612 SEQ ID NO: 201 AAV4-4 96 US20150315612 SEQ ID NO: 218 AAV44.1 97 US20030138772 SEQ ID NO: 46 AAV44.1 98 US20030138772 SEQ ID NO: 79 AAV44.5 99 US20030138772 SEQ ID NO: 47 AAV44.5 100 US20030138772 SEQ ID NO: 80 AAV4407 101 US20150315612 SEQ ID NO: 90 AAV5 102 U.S. Pat. No. 7,427,396 SEQ ID NO: 1 AAV5 103 US20030138772 SEQ ID NO: 114 AAV5 104 US20160017295 SEQ ID NO: 5, U.S. Pat. No. 7,427,396 SEQ ID NO: 2, US20150315612 SEQ ID NO: 216 AAV5 105 US20150315612 SEQ ID NO: 199 AAV6 106 US20150159173 SEQ ID NO: 13 AAV6 107 US20030138772 SEQ ID NO: 65, US20150159173 SEQ ID NO: 29, US20160017295 SEQ ID NO: 6, U.S. Pat. No. 6,156,303 SEQ ID NO: 7 AAV6 108 U.S. Pat. No. 6,156,303 SEQ ID NO: 11 AAV6 109 U.S. Pat. No. 6,156,303 SEQ ID NO: 2 AAV6 110 US20150315612 SEQ ID NO: 203 AAV6 111 US20150315612 SEQ ID NO: 220 AAV6.1 112 US20150159173 AAV6.12 113 US20150159173 AAV6.2 114 US20150159173 AAV7 115 US20150159173 SEQ ID NO: 14 AAV7 116 US20150315612 SEQ ID NO: 183 AAV7 117 US20030138772 SEQ ID NO: 2, US20150159173 SEQ ID NO: 30, US20150315612 SEQ ID NO: 181, US20160017295 SEQ ID NO: 7 AAV7 118 US20030138772 SEQ ID NO: 3 AAV7 119 US20030138772 SEQ ID NO: 1, US20150315612 SEQ ID NO: 180 AAV7 120 US20150315612 SEQ ID NO: 213 AAV7 121 US20150315612 SEQ ID NO: 222 AAV8 122 US20150159173 SEQ ID NO: 15 AAV8 123 US20150376240 SEQ ID NO: 7 AAV8 124 US20030138772 SEQ ID NO: 4, US20150315612 SEQ ID NO: 182 AAV8 125 US20030138772 SEQ ID NO: 95, US20140359799 SEQ ID NO: 1, US20150159173 SEQ ID NO: 31, US20160017295 SEQ ID NO: 8, U.S. Pat. No. 7,198,951 SEQ ID NO: 7, US20150315612 SEQ ID NO: 223 AAV8 126 US20150376240 SEQ ID NO: 8 AAV8 127 US20150315612 SEQ ID NO: 214 AAV-8b 128 US20150376240 SEQ ID NO: 5 AAV-8b 129 US20150376240 SEQ ID NO: 3 AAV-8h 130 US20150376240 SEQ ID NO: 6 AAV-8h 131 US20150376240 SEQ ID NO: 4 AAV9 132 US20030138772 SEQ ID NO: 5 AAV9 133 U.S. Pat. No. 7,198,951 SEQ ID NO: 1 AAV9 134 US20160017295 SEQ ID NO: 9 AAV9 135 US20030138772 SEQ ID NO: 100, U.S. Pat. No. 7,198,951 SEQ ID NO: 2 AAV9 136 U.S. Pat. No. 7,198,951 SEQ ID NO: 3 AAV9 (AAVhu.14) 137 U.S. Pat. No. 7,906,111 SEQ ID NO: 3; WO2015038958 SEQ ID NO: 11 AAV9 (AAVhu.14) 138 U.S. Pat. No. 7,906,111 SEQ ID NO: 123; WO2015038958 SEQ ID NO: 2 AAVA3.1 139 US20030138772 SEQ ID NO: 120 AAVA3.3 140 US20030138772 SEQ ID NO: 57 AAVA3.3 141 US20030138772 SEQ ID NO: 66 AAVA3.4 142 US20030138772 SEQ ID NO: 54 AAVA3.4 143 US20030138772 SEQ ID NO: 68 AAVA3.5 144 US20030138772 SEQ ID NO: 55 AAVA3.5 145 US20030138772 SEQ ID NO: 69 AAVA3.7 146 US20030138772 SEQ ID NO: 56 AAVA3.7 147 US20030138772 SEQ ID NO: 67 AAV29.3 (AAVbb.1) 148 US20030138772 SEQ ID NO: 11 AAVC2 149 US20030138772 SEQ ID NO: 61 AAVCh.5 150 US20150159173 SEQ ID NO: 46, US20150315612 SEQ ID NO: 234 AAVcy.2 (AAV13.3) 151 US20030138772 SEQ ID NO: 15 AAV24.1 152 US20030138772 SEQ ID NO: 101 AAVcy.3 (AAV24.1) 153 US20030138772 SEQ ID NO: 16 AAV27.3 154 US20030138772 SEQ ID NO: 104 AAVcy.4 (AAV27.3) 155 US20030138772 SEQ ID NO: 17 AAVcy.5 156 US20150315612 SEQ ID NO: 227 AAV7.2 157 US20030138772 SEQ ID NO: 103 AAVcy.5 (AAV7.2.) 158 US20030138772 SEQ ID NO: 18 AAV16.3 159 US20030138772 SEQ ID NO: 105 AAVcy.6 (AAV16.3) 160 US20030138772 SEQ ID NO: 10 AAVcy.5 161 US20150159173 SEQ ID NO: 8 AAVcy.5 162 US20150159173 SEQ ID NO: 24 AAVCy.5R1 163 US20150159173 AAVCy.5R2 164 US20150159173 AAVCy.5R3 165 US20150159173 AAVCy.5R4 166 US20150159173 AAVDJ 167 US20140359799 SEQ ID NO: 3, U.S. Pat. No. 7,588,772 SEQ ID NO: 2 AAVDJ 168 US20140359799 SEQ ID NO: 2, U.S. Pat. No. 7,588,772 SEQ ID NO: 1 AAVDJ-8 169 U.S. Pat. No. 7,588,772; Grimm et al 2008 AAVDJ-8 170 U.S. Pat. No. 7,588,772; Grimm et al 2008 AAVF5 171 US20030138772 SEQ ID NO: 110 AAVH2 172 US20030138772 SEQ ID NO: 26 AAVH6 173 US20030138772 SEQ ID NO: 25 AAVhE1.1 174 U.S. Pat. No. 9,233,131 SEQ ID NO: 44 AAVhEr1.14 175 U.S. Pat. No. 9,233,131 SEQ ID NO: 46 AAVhEr1.16 176 U.S. Pat. No. 9,233,131 SEQ ID NO: 48 AAVhEr1.18 177 U.S. Pat. No. 9,233,131 SEQ ID NO: 49 AAVhEr1.23 (AAVhEr2.29) 178 U.S. Pat. No. 9,233,131 SEQ ID NO: 53 AAVhEr1.35 179 U.S. Pat. No. 9,233,131 SEQ ID NO: 50 AAVhEr1.36 180 U.S. Pat. No. 9,233,131 SEQ ID NO: 52 AAVhEr1.5 181 U.S. Pat. No. 9,233,131 SEQ ID NO: 45 AAVhEr1.7 182 U.S. Pat. No. 9,233,131 SEQ ID NO: 51 AAVhEr1.8 183 U.S. Pat. No. 9,233,131 SEQ ID NO: 47 AAVhEr2.16 184 U.S. Pat. No. 9,233,131 SEQ ID NO: 55 AAVhEr2.30 185 U.S. Pat. No. 9,233,131 SEQ ID NO: 56 AAVhEr2.31 186 U.S. Pat. No. 9,233,131 SEQ ID NO: 58 AAVhEr2.36 187 U.S. Pat. No. 9,233,131 SEQ ID NO: 57 AAVhEr2.4 188 U.S. Pat. No. 9,233,131 SEQ ID NO: 54 AAVhEr3.1 189 U.S. Pat. No. 9,233,131 SEQ ID NO: 59 AAVhu.1 190 US20150315612 SEQ ID NO: 46 AAVhu.1 191 US20150315612 SEQ ID NO: 144 AAVhu.10 (AAV16.8) 192 US20150315612 SEQ ID NO: 56 AAVhu.10 (AAV16.8) 193 US20150315612 SEQ ID NO: 156 AAVhu.11 (AAV16.12) 194 US20150315612 SEQ ID NO: 57 AAVhu.11 (AAV16.12) 195 US20150315612 SEQ ID NO: 153 AAVhu.12 196 US20150315612 SEQ ID NO: 59 AAVhu.12 197 US20150315612 SEQ ID NO: 154 AAVhu.13 198 US20150159173 SEQ ID NO: 16, US20150315612 SEQ ID NO: 71 AAVhu.13 199 US20150159173 SEQ ID NO: 32, US20150315612 SEQ ID NO: 129 AAVhu.136.1 200 US20150315612 SEQ ID NO: 165 AAVhu.140.1 201 US20150315612 SEQ ID NO: 166 AAVhu.140.2 202 US20150315612 SEQ ID NO: 167 AAVhu.145.6 203 US20150315612 SEQ ID No: 178 AAVhu.15 204 US20150315612 SEQ ID NO: 147 AAVhu.15 (AAV33.4) 205 US20150315612 SEQ ID NO: 50 AAVhu.156.1 206 US20150315612 SEQ ID No: 179 AAVhu.16 207 US20150315612 SEQ ID NO: 148 AAVhu.16 (AAV33.8) 208 US20150315612 SEQ ID NO: 51 AAVhu.17 209 US20150315612 SEQ ID NO: 83 AAVhu.17 (AAV33.12) 210 US20150315612 SEQ ID NO: 4 AAVhu.172.1 211 US20150315612 SEQ ID NO: 171 AAVhu.172.2 212 US20150315612 SEQ ID NO: 172 AAVhu.173.4 213 US20150315612 SEQ ID NO: 173 AAVhu.173.8 214 US20150315612 SEQ ID NO: 175 AAVhu.18 215 US20150315612 SEQ ID NO: 52 AAVhu.18 216 US20150315612 SEQ ID NO: 149 AAVhu.19 217 US20150315612 SEQ ID NO: 62 AAVhu.19 218 US20150315612 SEQ ID NO: 133 AAVhu.2 219 US20150315612 SEQ ID NO: 48 AAVhu.2 220 US20150315612 SEQ ID NO: 143 AAVhu.20 221 US20150315612 SEQ ID NO: 63 AAVhu.20 222 US20150315612 SEQ ID NO: 134 AAVhu.21 223 US20150315612 SEQ ID NO: 65 AAVhu.21 224 US20150315612 SEQ ID NO: 135 AAVhu.22 225 US20150315612 SEQ ID NO: 67 AAVhu.22 226 US20150315612 SEQ ID NO: 138 AAVhu.23 227 US20150315612 SEQ ID NO: 60 AAVhu.23.2 228 US20150315612 SEQ ID NO: 137 AAVhu.24 229 US20150315612 SEQ ID NO: 66 AAVhu.24 230 US20150315612 SEQ ID NO: 136 AAVhu.25 231 US20150315612 SEQ ID NO: 49 AAVhu.25 232 US20150315612 SEQ ID NO: 146 AAVhu.26 233 US20150159173 SEQ ID NO: 17, US20150315612 SEQ ID NO: 61 AAVhu.26 234 US20150159173 SEQ ID NO: 33, US20150315612 SEQ ID NO: 139 AAVhu.27 235 US20150315612 SEQ ID NO: 64 AAVhu.27 236 US20150315612 SEQ ID NO: 140 AAVhu.28 237 US20150315612 SEQ ID NO: 68 AAVhu.28 238 US20150315612 SEQ ID NO: 130 AAVhu.29 239 US20150315612 SEQ ID NO: 69 AAVhu.29 240 US20150159173 SEQ ID NO: 42, US20150315612 SEQ ID NO: 132 AAVhu.29 241 US20150315612 SEQ ID NO: 225 AAVhu.29R 242 US20150159173 AAVhu.3 243 US20150315612 SEQ ID NO: 44 AAVhu.3 244 US20150315612 SEQ ID NO: 145 AAVhu.30 245 US20150315612 SEQ ID NO: 70 AAVhu.30 246 US20150315612 SEQ ID NO: 131 AAVhu.31 247 US20150315612 SEQ ID NO: 1 AAVhu.31 248 US20150315612 SEQ ID NO: 121 AAVhu.32 249 US20150315612 SEQ ID NO: 2 AAVhu.32 250 US20150315612 SEQ ID NO: 122 AAVhu.33 251 US20150315612 SEQ ID NO: 75 AAVhu.33 252 US20150315612 SEQ ID NO: 124 AAVhu.34 253 US20150315612 SEQ ID NO: 72 AAVhu.34 254 US20150315612 SEQ ID NO: 125 AAVhu.35 255 US20150315612 SEQ ID NO: 73 AAVhu.35 256 US20150315612 SEQ ID NO: 164 AAVhu.36 257 US20150315612 SEQ ID NO: 74 AAVhu.36 258 US20150315612 SEQ ID NO: 126 AAVhu.37 259 US20150159173 SEQ ID NO: 34, US20150315612 SEQ ID NO: 88 AAVhu.37 (AAV106.1) 260 US20150315612 SEQ ID NO: 10, US20150159173 SEQ ID NO: 18 AAVhu.38 261 US20150315612 SEQ ID NO: 161 AAVhu.39 262 US20150315612 SEQ ID NO: 102 AAVhu.39 (AAVLG-9) 263 US20150315612 SEQ ID NO: 24 AAVhu.4 264 US20150315612 SEQ ID NO: 47 AAVhu.4 265 US20150315612 SEQ ID NO: 141 AAVhu.40 266 US20150315612 SEQ ID NO: 87 AAVhu.40 (AAV114.3) 267 US20150315612 SEQ ID No. 11 AAVhu.41 268 US20150315612 SEQ ID NO: 91 AAVhu.41 (AAV127.2) 269 US20150315612 SEQ ID NO: 6 AAVhu.42 270 US20150315612 SEQ ID NO: 85 AAVhu.42 (AAV127.5) 271 US20150315612 SEQ ID NO: 8 AAVhu.43 272 US20150315612 SEQ ID NO: 160 AAVhu.43 273 US20150315612 SEQ ID NO: 236 AAVhu.43 (AAV128.1) 274 US20150315612 SEQ ID NO: 80 AAVhu.44 275 US20150159173 SEQ ID NO: 45, US20150315612 SEQ ID NO: 158 AAVhu.44 (AAV128.3) 276 US20150315612 SEQ ID NO: 81 AAVhu.44R1 277 US20150159173 AAVhu.44R2 278 US20150159173 AAVhu.44R3 279 US20150159173 AAVhu.45 280 US20150315612 SEQ ID NO: 76 AAVhu.45 281 US20150315612 SEQ ID NO: 127 AAVhu.46 282 US20150315612 SEQ ID NO: 82 AAVhu.46 283 US20150315612 SEQ ID NO: 159 AAVhu.46 284 US20150315612 SEQ ID NO: 224 AAVhu.47 285 US20150315612 SEQ ID NO: 77 AAVhu.47 286 US20150315612 SEQ ID NO: 128 AAVhu.48 287 US20150159173 SEQ ID NO: 38 AAVhu.48 288 US20150315612 SEQ ID NO: 157 AAVhu.48 (AAV130.4) 289 US20150315612 SEQ ID NO: 78 AAVhu.48R1 290 US20150159173 AAVhu.48R2 291 US20150159173 AAVhu.48R3 292 US20150159173 AAVhu.49 293 US20150315612 SEQ ID NO: 209 AAVhu.49 294 US20150315612 SEQ ID NO: 189 AAVhu.5 295 US20150315612 SEQ ID NO: 45 AAVhu.5 296 US20150315612 SEQ ID NO: 142 AAVhu.51 297 US20150315612 SEQ ID NO: 208 AAVhu.51 298 US20150315612 SEQ ID NO: 190 AAVhu.52 299 US20150315612 SEQ ID NO: 210 AAVhu.52 300 US20150315612 SEQ ID NO: 191 AAVhu.53 301 US20150159173 SEQ ID NO: 19 AAVhu.53 302 US20150159173 SEQ ID NO: 35 AAVhu.53 (AAV145.1) 303 US20150315612 SEQ ID NO: 176 AAVhu.54 304 US20150315612 SEQ ID NO: 188 AAVhu.54 (AAV145.5) 305 US20150315612 SEQ ID No: 177 AAVhu.55 306 US20150315612 SEQ ID NO: 187 AAVhu.56 307 US20150315612 SEQ ID NO: 205 AAVhu.56 (AAV145.6) 308 US20150315612 SEQ ID NO: 168 AAVhu.56 (AAV145.6) 309 US20150315612 SEQ ID NO: 192 AAVhu.57 310 US20150315612 SEQ ID NO: 206 AAVhu.57 311 US20150315612 SEQ ID NO: 169 AAVhu.57 312 US20150315612 SEQ ID NO: 193 AAVhu.58 313 US20150315612 SEQ ID NO: 207 AAVhu.58 314 US20150315612 SEQ ID NO: 194 AAVhu.6 (AAV3.1) 315 US20150315612 SEQ ID NO: 5 AAVhu.6 (AAV3.1) 316 US20150315612 SEQ ID NO: 84 AAVhu.60 317 US20150315612 SEQ ID NO: 184 AAVhu.60 (AAV161.10) 318 US20150315612 SEQ ID NO: 170 AAVhu.61 319 US20150315612 SEQ ID NO: 185 AAVhu.61 (AAV161.6) 320 US20150315612 SEQ ID NO: 174 AAVhu.63 321 US20150315612 SEQ ID NO: 204 AAVhu.63 322 US20150315612 SEQ ID NO: 195 AAVhu.64 323 US20150315612 SEQ ID NO: 212 AAVhu.64 324 US20150315612 SEQ ID NO: 196 AAVhu.66 325 US20150315612 SEQ ID NO: 197 AAVhu.67 326 US20150315612 SEQ ID NO: 215 AAVhu.67 327 US20150315612 SEQ ID NO: 198 AAVhu.7 328 US20150315612 SEQ ID NO: 226 AAVhu.7 329 US20150315612 SEQ ID NO: 150 AAVhu.7 (AAV7.3) 330 US20150315612 SEQ ID NO: 55 AAVhu.71 331 US20150315612 SEQ ID NO: 79 AAVhu.8 332 US20150315612 SEQ ID NO: 53 AAVhu.8 333 US20150315612 SEQ ID NO: 12 AAVhu.8 334 US20150315612 SEQ ID NO: 151 AAVhu.9 (AAV3.1) 335 US20150315612 SEQ ID NO: 58 AAVhu.9 (AAV3.1) 336 US20150315612 SEQ ID NO: 155 AAV-LK01 337 US20150376607 SEQ ID NO: 2 AAV-LK01 338 US20150376607 SEQ ID NO: 29 AAV-LK02 339 US20150376607 SEQ ID NO: 3 AAV-LK02 340 US20150376607 SEQ ID NO: 30 AAV-LK03 341 US20150376607 SEQ ID NO: 4 AAV-LK03 342 WO2015121501 SEQ ID NO: 12, US20150376607 SEQ ID NO: 31 AAV-LK04 343 US20150376607 SEQ ID NO: 5 AAV-LK04 344 US20150376607 SEQ ID NO: 32 AAV-LK05 345 US20150376607 SEQ ID NO: 6 AAV-LK05 346 US20150376607 SEQ ID NO: 33 AAV-LK06 347 US20150376607 SEQ ID NO: 7 AAV-LK06 348 US20150376607 SEQ ID NO: 34 AAV-LK07 349 US20150376607 SEQ ID NO: 8 AAV-LK07 350 US20150376607 SEQ ID NO: 35 AAV-LK08 351 US20150376607 SEQ ID NO: 9 AAV-LK08 352 US20150376607 SEQ ID NO: 36 AAV-LK09 353 US20150376607 SEQ ID NO: 10 AAV-LK09 354 US20150376607 SEQ ID NO: 37 AAV-LK10 355 US20150376607 SEQ ID NO: 11 AAV-LK10 356 US20150376607 SEQ ID NO: 38 AAV-LK11 357 US20150376607 SEQ ID NO: 12 AAV-LK11 358 US20150376607 SEQ ID NO: 39 AAV-LK12 359 US20150376607 SEQ ID NO: 13 AAV-LK12 360 US20150376607 SEQ ID NO: 40 AAV-LK13 361 US20150376607 SEQ ID NO: 14 AAV-LK13 362 US20150376607 SEQ ID NO: 41 AAV-LK14 363 US20150376607 SEQ ID NO: 15 AAV-LK14 364 US20150376607 SEQ ID NO: 42 AAV-LK15 365 US20150376607 SEQ ID NO: 16 AAV-LK15 366 US20150376607 SEQ ID NO: 43 AAV-LK16 367 US20150376607 SEQ ID NO: 17 AAV-LK16 368 US20150376607 SEQ ID NO: 44 AAV-LK17 369 US20150376607 SEQ ID NO: 18 AAV-LK17 370 US20150376607 SEQ ID NO: 45 AAV-LK18 371 US20150376607 SEQ ID NO: 19 AAV-LK18 372 US20150376607 SEQ ID NO: 46 AAV-LK19 373 US20150376607 SEQ ID NO: 20 AAV-LK19 374 US20150376607 SEQ ID NO: 47 AAV-PAEC 375 US20150376607 SEQ ID NO: 1 AAV-PAEC 376 US20150376607 SEQ ID NO: 48 AAV-PAEC11 377 US20150376607 SEQ ID NO: 26 AAV-PAEC11 378 US20150376607 SEQ ID NO: 54 AAV-PAEC12 379 US20150376607 SEQ ID NO: 27 AAV-PAEC12 380 US20150376607 SEQ ID NO: 51 AAV-PAEC13 381 US20150376607 SEQ ID NO: 28 AAV-PAEC13 382 US20150376607 SEQ ID NO: 49 AAV-PAEC2 383 US20150376607 SEQ ID NO: 21 AAV-PAEC2 384 US20150376607 SEQ ID NO: 56 AAV-PAEC4 385 US20150376607 SEQ ID NO: 22 AAV-PAEC4 386 US20150376607 SEQ ID NO: 55 AAV-PAEC6 387 US20150376607 SEQ ID NO: 23 AAV-PAEC6 388 US20150376607 SEQ ID NO: 52 AAV-PAEC7 389 US20150376607 SEQ ID NO: 24 AAV-PAEC7 390 US20150376607 SEQ ID NO: 53 AAV-PAEC8 391 US20150376607 SEQ ID NO: 25 AAV-PAEC8 392 US20150376607 SEQ ID NO: 50 AAVpi.1 393 US20150315612 SEQ ID NO: 28 AAVpi.1 394 US20150315612 SEQ ID NO: 93 AAVpi.2 395 US20150315612 SEQ ID NO: 30 AAVpi.2 396 US20150315612 SEQ ID NO: 95 AAVpi.3 397 US20150315612 SEQ ID NO: 29 AAVpi.3 398 US20150315612 SEQ ID NO: 94 AAVrh.10 399 US20150159173 SEQ ID NO: 9 AAVrh.10 400 US20150159173 SEQ ID NO: 25 AAV44.2 401 US20030138772 SEQ ID NO: 59 AAVrh.10 (AAV44.2) 402 US20030138772 SEQ ID NO: 81 AAV42.1B 403 US20030138772 SEQ ID NO: 90 AAVrh.12 (AAV42.1b) 404 US20030138772 SEQ ID NO: 30 AAVrh.13 405 US20150159173 SEQ ID NO: 10 AAVrh.13 406 US20150159173 SEQ ID NO: 26 AAVrh.13 407 US20150315612 SEQ ID NO: 228 AAVrh.13R 408 US20150159173 AAV42.3A 409 US20030138772 SEQ ID NO: 87 AAVrh.14 (AAV42.3a) 410 US20030138772 SEQ ID NO: 32 AAV42.5A 411 US20030138772 SEQ ID NO: 89 AAVrh.17 (AAV42.5a) 412 US20030138772 SEQ ID NO: 34 AAV42.5B 413 US20030138772 SEQ ID NO: 91 AAVrh.18 (AAV42.5b) 414 US20030138772 SEQ ID NO: 29 AAV42.6B 415 US20030138772 SEQ ID NO: 112 AAVrh.19 (AAV42.6b) 416 US20030138772 SEQ ID NO: 38 AAVrh.2 417 US20150159173 SEQ ID NO: 39 AAVrh.2 418 US20150315612 SEQ ID NO: 231 AAVrh.20 419 US20150159173 SEQ ID NO: 1 AAV42.10 420 US20030138772 SEQ ID NO: 106 AAVrh.21 (AAV42.10) 421 US20030138772 SEQ ID NO: 35 AAV42.11 422 US20030138772 SEQ ID NO: 108 AAVrh.22 (AAV42.11) 423 US20030138772 SEQ ID NO: 37 AAV42.12 424 US20030138772 SEQ ID NO: 113 AAVrh.23 (AAV42.12) 425 US20030138772 SEQ ID NO: 58 AAV42.13 426 US20030138772 SEQ ID NO: 86 AAVrh.24 (AAV42.13) 427 US20030138772 SEQ ID NO: 31 AAV42.15 428 US20030138772 SEQ ID NO: 84 AAVrh.25 (AAV42.15) 429 US20030138772 SEQ ID NO: 28 AAVrh.2R 430 US20150159173 AAVrh.31 (AAV223.1) 431 US20030138772 SEQ ID NO: 48 AAVC1 432 US20030138772 SEQ ID NO: 60 AAVrh.32 (AAVC1) 433 US20030138772 SEQ ID NO: 19 AAVrh.32/33 434 US20150159173 SEQ ID NO: 2 AAVrh.33 (AAVC3) 435 US20030138772 SEQ ID NO: 20 AAVC5 436 US20030138772 SEQ ID NO: 62 AAVrh.34 (AAVC5) 437 US20030138772 SEQ ID NO: 21 AAVF1 438 US20030138772 SEQ ID NO: 109 AAVrh.35 (AAVF1) 439 US20030138772 SEQ ID NO: 22 AAVF3 440 US20030138772 SEQ ID NO: 111 AAVrh.36 (AAVF3) 441 US20030138772 SEQ ID NO: 23 AAVrh.37 442 US20030138772 SEQ ID NO: 24 AAVrh.37 443 US20150159173 SEQ ID NO: 40 AAVrh.37 444 US20150315612 SEQ ID NO: 229 AAVrh.37R2 445 US20150159173 AAVrh.38 (AAVLG-4) 446 US20150315612 SEQ ID NO: 7 AAVrh.38 (AAVLG-4) 447 US20150315612 SEQ ID NO: 86 AAVrh.39 448 US20150159173 SEQ ID NO: 20, US20150315612 SEQ ID NO: 13 AAVrh.39 449 US20150159173 SEQ ID NO: 3, US20150159173 SEQ ID NO: 36, US20150315612 SEQ ID NO: 89 AAVrh.40 450 US20150315612 SEQ ID NO: 92 AAVrh.40 (AAVLG-10) 451 US20150315612 SEQ ID No: 14 AAVrh.43 (AAVN721-8) 452 US20150315612 SEQ ID NO: 43, US20150159173 SEQ ID NO: 21 AAVrh.43 (AAVN721-8) 453 US20150315612 SEQ ID NO: 163, US20150159173 SEQ ID NO: 37 AAVrh.44 454 US20150315612 SEQ ID NO: 34 AAVrh.44 455 US20150315612 SEQ ID NO: 111 AAVrh.45 456 US20150315612 SEQ ID NO: 41 AAVrh.45 457 US20150315612 SEQ ID NO: 109 AAVrh.46 458 US20150159173 SEQ ID NO: 22, US20150315612 SEQ ID NO: 19 AAVrh.46 459 US20150159173 SEQ ID NO: 4, US20150315612 SEQ ID NO: 101 AAVrh.47 460 US20150315612 SEQ ID NO: 38 AAVrh.47 461 US20150315612 SEQ ID NO: 118 AAVrh.48 462 US20150159173 SEQ ID NO: 44, US20150315612 SEQ ID NO: 115 AAVrh.48.1 463 US20150159173 AAVrh.48.1.2 464 US20150159173 AAVrh.48.2 465 US20150159173 AAVrh.48 (AAV1-7) 466 US20150315612 SEQ ID NO: 32 AAVrh.49 (AAV1-8) 467 US20150315612 SEQ ID NO: 25 AAVrh.49 (AAV1-8) 468 US20150315612 SEQ ID NO: 103 AAVrh.50 (AAV2-4) 469 US20150315612 SEQ ID NO: 23 AAVrh.50 (AAV2-4) 470 US20150315612 SEQ ID NO: 108 AAVrh.51 (AAV2-5) 471 US20150315612 SEQ ID No: 22 AAVrh.51 (AAV2-5) 472 US20150315612 SEQ ID NO: 104 AAVrh.52 (AAV3-9) 473 US20150315612 SEQ ID NO: 18 AAVrh.52 (AAV3-9) 474 US20150315612 SEQ ID NO: 96 AAVrh.53 475 US20150315612 SEQ ID NO: 97 AAVrh.53 (AAV3-11) 476 US20150315612 SEQ ID NO: 17 AAVrh.53 (AAV3-11) 477 US20150315612 SEQ ID NO: 186 AAVrh.54 478 US20150315612 SEQ ID NO: 40 AAVrh.54 479 US20150159173 SEQ ID NO: 49, US20150315612 SEQ ID NO: 116 AAVrh.55 480 US20150315612 SEQ ID NO: 37 AAVrh.55 (AAV4-19) 481 US20150315612 SEQ ID NO: 117 AAVrh.56 482 US20150315612 SEQ ID NO: 54 AAVrh.56 483 US20150315612 SEQ ID NO: 152 AAVrh.57 484 US20150315612 SEQ ID NO: 26 AAVrh.57 485 US20150315612 SEQ ID NO: 105 AAVrh.58 486 US20150315612 SEQ ID NO: 27 AAVrh.58 487 US20150159173 SEQ ID NO: 48, US20150315612 SEQ ID NO: 106 AAVrh.58 488 US20150315612 SEQ ID NO: 232 AAVrh.59 489 US20150315612 SEQ ID NO: 42 AAVrh.59 490 US20150315612 SEQ ID NO: 110 AAVrh.60 491 US20150315612 SEQ ID NO: 31 AAVrh.60 492 US20150315612 SEQ ID NO: 120 AAVrh.61 493 US20150315612 SEQ ID NO: 107 AAVrh.61 (AAV2-3) 494 US20150315612 SEQ ID NO: 21 AAVrh.62 (AAV2-15) 495 US20150315612 SEQ ID No: 33 AAVrh.62 (AAV2-15) 496 US20150315612 SEQ ID NO: 114 AAVrh.64 497 US20150315612 SEQ ID No: 15 AAVrh.64 498 US20150159173 SEQ ID NO: 43, US20150315612 SEQ ID NO: 99 AAVrh.64 499 US20150315612 SEQ ID NO: 233 AAVRh.64R1 500 US20150159173 AAVRh.64R2 501 US20150159173 AAVrh.65 502 US20150315612 SEQ ID NO: 35 AAVrh.65 503 US20150315612 SEQ ID NO: 112 AAVrh.67 504 US20150315612 SEQ ID NO: 36 AAVrh.67 505 US20150315612 SEQ ID NO: 230 AAVrh.67 506 US20150159173 SEQ ID NO: 47, US20150315612 SEQ ID NO: 113 AAVrh.68 507 US20150315612 SEQ ID NO: 16 AAVrh.68 508 US20150315612 SEQ ID NO: 100 AAVrh.69 509 US20150315612 SEQ ID NO: 39 AAVrh.69 510 US20150315612 SEQ ID NO: 119 AAVrh.70 511 US20150315612 SEQ ID NO: 20 AAVrh.70 512 US20150315612 SEQ ID NO: 98 AAVrh.71 513 US20150315612 SEQ ID NO: 162 AAVrh.72 514 US20150315612 SEQ ID NO: 9 AAVrh.73 515 US20150159173 SEQ ID NO: 5 AAVrh.74 516 US20150159173 SEQ ID NO: 6 AAVrh.8 517 US20150159173 SEQ ID NO: 41 AAVrh.8 518 US20150315612 SEQ ID NO: 235 AAVrh.8R 519 US20150159173, WO2015168666 SEQ ID NO: 9 AAVrh.8R A586R mutant 520 WO2015168666 SEQ ID NO: 10 AAVrh.8R R533A mutant 521 WO2015168666 SEQ ID NO: 11 BAAV (bovine AAV) 522 U.S. Pat. No. 9,193,769 SEQ ID NO: 8 BAAV (bovine AAV) 523 U.S. Pat. No. 9,193,769 SEQ ID NO: 10 BAAV (bovine AAA) 524 U.S. Pat. No. 9,193,769 SEQ ID NO: 4 BAAV (bovine AAV) 525 U.S. Pat. No. 9,193,769 SEQ ID NO: 2 BAAV (bovine AAV) 526 U.S. Pat. No. 9,193,769 SEQ ID NO: 6 BAAV (bovine AAV) 527 U.S. Pat. No. 9,193,769 SEQ ID NO: 1 BAAV (bovine AAV) 528 U.S. Pat. No. 9,193,769 SEQ ID NO: 5 BAAV (bovine AAV) 529 U.S. Pat. No. 9,193,769 SEQ ID NO: 3 BAAV (bovine AAV) 530 U.S. Pat. No. 9,193,769 SEQ ID NO: 11 BAAV (bovine AAA) 531 U.S. Pat. No. 7,427,396 SEQ ID NO: 5 BAAV (bovine AAV) 532 U.S. Pat. No. 7,427,396 SEQ ID NO: 6 BAAV (bovine AAV) 533 U.S. Pat. No. 9,193,769 SEQ ID NO: 7 BAAV (bovine AAV) 534 U.S. Pat. No. 9,193,769 SEQ ID NO: 9 BNP61 AAV 535 US20150238550 SEQ ID NO: 1 BNP61 AAV 536 US20150238550 SEQ ID NO: 2 BNP62 AAV 537 US20150238550 SEQ ID NO: 3 BNP63 AAV 538 US20150238550 SEQ ID NO: 4 caprine AAV 539 U.S. Pat. No. 7,427,396 SEQ ID NO: 3 caprine AAV 540 U.S. Pat. No. 7,427,396 SEQ ID NO: 4 true type AAV (ttAAV) 541 WO2015121501 SEQ ID NO: 2 AAAV (Avian AAV) 542 U.S. Pat. No. 9,238,800 SEQ ID NO: 12 AAAV (Avian AAV) 543 U.S. Pat. No. 9,238,800 SEQ ID NO: 2 AAAV (Avian AAV) 544 U.S. Pat. No. 9,238,800 SEQ ID NO: 6 AAAV (Avian AAV) 545 U.S. Pat. No. 9,238,800 SEQ ID NO: 4 AAAV (Avian AAV) 546 U.S. Pat. No. 9,238,800 SEQ ID NO: 8 AAAV (Avian AAV) 547 U.S. Pat. No. 9,238,800 SEQ ID NO: 14 AAAV (Avian AAV) 548 U.S. Pat. No. 9,238,800 SEQ ID NO: 10 AAAV (Avian AAV) 549 U.S. Pat. No. 9,238,800 SEQ ID NO: 15 AAAV (Avian AAV) 550 U.S. Pat. No. 9,238,800 SEQ ID NO: 5 AAAV (Avian AAV) 551 U.S. Pat. No. 9,238,800 SEQ ID NO: 9 AAAV (Avian AAV) 552 U.S. Pat. No. 9,238,800 SEQ ID NO: 3 AAAV (Avian AAV) 553 U.S. Pat. No. 9,238,800 SEQ ID NO: 7 AAAV (Avian AAV) 554 U.S. Pat. No. 9,238,800 SEQ ID NO: 11 AAAV (Avian AAV) 555 U.S. Pat. No. 9,238,800 SEQ ID NO: 13 AAAV (Avian AAV) 556 U.S. Pat. No. 9,238,800 SEQ ID NO: 1 AAV Shuffle 100-1 557 US20160017295 SEQ ID NO: 23 AAV Shuffle 100-1 558 US20160017295 SEQ ID NO: 11 AAV Shuffle 100-2 559 US20160017295 SEQ ID NO: 37 AAV Shuffle 100-2 560 US20160017295 SEQ ID NO: 29 AAV Shuffle 100-3 561 US20160017295 SEQ ID NO: 24 AAV Shuffle 100-3 562 US20160017295 SEQ ID NO: 12 AAV Shuffle 100-7 563 US20160017295 SEQ ID NO: 25 AAV Shuffle 100-7 564 US20160017295 SEQ ID NO: 13 AAV Shuffle 10-2 565 US20160017295 SEQ ID NO: 34 AAV Shuffle 10-2 566 US20160017295 SEQ ID NO: 26 AAV Shuffle 10-6 567 US20160017295 SEQ ID NO: 35 AAV Shuffle 10-6 568 US20160017295 SEQ ID NO: 27 AAV Shuffle 10-8 569 US20160017295 SEQ ID NO: 36 AAV Shuffle 10-8 570 US20160017295 SEQ ID NO: 28 AAV SM 100-10 571 US20160017295 SEQ ID NO: 41 AAV SM 100-10 572 US20160017295 SEQ ID NO: 33 AAV SM 100-3 573 US20160017295 SEQ ID NO: 40 AAV SM 100-3 574 US20160017295 SEQ ID NO: 32 AAV SM 10-1 575 US20160017295 SEQ ID NO: 38 AAV SM 10-1 576 US20160017295 SEQ ID NO: 30 AAV SM 10-2 577 US20160017295 SEQ ID NO: 10 AAV SM 10-2 578 US20160017295 SEQ ID NO: 22 AAV SM 10-8 579 US20160017295 SEQ ID NO: 39 AAV SM 10-8 580 US20160017295 SEQ ID NO: 31 AAVF1/HSC1 581 WO2016049230 SEQ ID NO: 20 AAVF2/HSC2 582 WO2016049230 SEQ ID NO: 21 AAVF3/HSC3 583 WO2016049230 SEQ ID NO: 22 AAVF4/HSC4 584 WO2016049230 SEQ ID NO: 23 AAVF5/HSC5 585 WO2016049230 SEQ ID NO: 25 AAVF6/HSC6 586 WO2016049230 SEQ ID NO: 24 AAVF7/HSC7 587 WO2016049230 SEQ ID NO: 27 AAVF8/HSC8 588 WO2016049230 SEQ ID NO: 28 AAVF9/HSC9 589 WO2016049230 SEQ ID NO: 29 AAVF11/HSC11 590 WO2016049230 SEQ ID NO: 26 AAVF12/HSC12 591 WO2016049230 SEQ ID NO: 30 AAVF13/HSC13 592 WO2016049230 SEQ ID NO: 31 AAVF14/HSC14 593 WO2016049230 SEQ ID NO: 32 AAVF15/HSC15 594 WO2016049230 SEQ ID NO: 33 AAVF16/HSC16 595 WO2016049230 SEQ ID NO: 34 AAVF17/HSC17 596 WO2016049230 SEQ ID NO: 35 AAVF1/HSC1 597 WO2016049230 SEQ ID NO: 2 AAVF2/HSC2 598 WO2016049230 SEQ ID NO: 3 AAVF3/HSC3 599 WO2016049230 SEQ ID NO: 5 AAVF4/HSC4 600 WO2016049230 SEQ ID NO: 6 AAVF5/HSC5 601 WO2016049230 SEQ ID NO: 11 AAVF6/HSC6 602 WO2016049230 SEQ ID NO: 7 AAVF7/HSC7 603 WO2016049230 SEQ ID NO: 8 AAVF8/HSC8 604 WO2016049230 SEQ ID NO: 9 AAVF9/HSC9 605 WO2016049230 SEQ ID NO: 10 AAVF11/HSC11 606 WO2016049230 SEQ ID NO: 4 AAVF12/HSC12 607 WO2016049230 SEQ ID NO: 12 AAVF13/HSC13 608 WO2016049230 SEQ ID NO: 14 AAVF14/HSC14 609 WO2016049230 SEQ ID NO: 15 AAVF15/HSC15 610 WO2016049230 SEQ ID NO: 16 AAVF16/HSC16 611 WO2016049230 SEQ ID NO: 17 AAVF17/HSC17 612 WO2016049230 SEQ ID NO: 13 AAV CBr-E1 613 U.S. Pat. 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No. 8,734,809 SEQ ID NO: 160 AAV CHt-P2 779 WO2016065001 SEQ ID NO: 1 AAV CHt-P5 780 WO2016065001 SEQ ID NO: 2 AAV CHt-P9 781 WO2016065001 SEQ ID NO: 3 AAV CBr-7.1 782 WO2016065001 SEQ ID NO: 4 AAV CBr-7.2 783 WO2016065001 SEQ ID NO: 5 AAV CBr-7.3 784 WO2016065001 SEQ ID NO: 6 AAV CBr-7.4 785 WO2016065001 SEQ ID NO: 7 AAV CBr-7.5 786 WO2016065001 SEQ ID NO: 8 AAV CBr-7.7 787 WO2016065001 SEQ ID NO: 9 AAV CBr-7.8 788 WO2016065001 SEQ ID NO: 10 AAV CBr-7.10 789 WO2016065001 SEQ ID NO: 11 AAV CKd-N3 790 WO2016065001 SEQ ID NO: 12 AAV CKd-N4 791 WO2016065001 SEQ ID NO: 13 AAV CKd-N9 792 WO2016065001 SEQ ID NO: 14 AAV CLv-L4 793 WO2016065001 SEQ ID NO: 15 AAV CLv-L5 794 WO2016065001 SEQ ID NO: 16 AAV CLv-L6 795 WO2016065001 SEQ ID NO: 17 AAV CLv-K1 796 WO2016065001 SEQ ID NO: 18 AAV CLv-K3 797 WO2016065001 SEQ ID NO: 19 AAV CLv-K6 798 WO2016065001 SEQ ID NO: 20 AAV CLv-M1 799 WO2016065001 SEQ ID NO: 21 AAV CLv-M11 800 WO2016065001 SEQ ID NO: 22 AAV CLv-M2 801 WO2016065001 SEQ ID NO: 23 AAV CLv-M5 802 WO2016065001 SEQ ID NO: 24 AAV CLv-M6 803 WO2016065001 SEQ ID NO: 25 AAV CLv-M7 804 WO2016065001 SEQ ID NO: 26 AAV CLv-M8 805 WO2016065001 SEQ ID NO: 27 AAV CLv-M9 806 WO2016065001 SEQ ID NO: 28 AAV CHt-P1 807 WO2016065001 SEQ ID NO: 29 AAV CHt-P6 808 WO2016065001 SEQ ID NO: 30 AAV CHt-P8 809 WO2016065001 SEQ ID NO: 31 AAV CHt-6.1 810 WO2016065001 SEQ ID NO: 32 AAV CHt-6.10 811 WO2016065001 SEQ ID NO: 33 AAV CHt-6.5 812 WO2016065001 SEQ ID NO: 34 AAV CHt-6.6 813 WO2016065001 SEQ ID NO: 35 AAV CHt-6.7 814 WO2016065001 SEQ ID NO: 36 AAV CHt-6.8 815 WO2016065001 SEQ ID NO: 37 AAV CSp-8.10 816 WO2016065001 SEQ ID NO: 38 AAV CSp-8.2 817 WO2016065001 SEQ ID NO: 39 AAV CSp-8.4 818 WO2016065001 SEQ ID NO: 40 AAV CSp-8.5 819 WO2016065001 SEQ ID NO: 41 AAV CSp-8.6 820 WO2016065001 SEQ ID NO: 42 AAV CSp-8.7 821 WO2016065001 SEQ ID NO: 43 AAV CSp-8.8 822 WO2016065001 SEQ ID NO: 44 AAV CSp-8.9 823 WO2016065001 SEQ ID NO: 45 AAV CBr-B7.3 824 WO2016065001 SEQ ID NO: 46 AAV CBr-B7.4 825 WO2016065001 SEQ ID NO: 47 AAV3B 826 WO2016065001 SEQ ID NO: 48 AAV4 827 WO2016065001 SEQ ID NO: 49 AAV5 828 WO2016065001 SEQ ID NO: 50 AAV CHt-P2 829 WO2016065001 SEQ ID NO: 51 AAV CHt-P5 830 WO2016065001 SEQ ID NO: 52 AAV CHt-P9 831 WO2016065001 SEQ ID NO: 53 AAV CBr-7.1 832 WO2016065001 SEQ ID NO: 54 AAV CBr-7.2 833 WO2016065001 SEQ ID NO: 55 AAV CBr-7.3 834 WO2016065001 SEQ ID NO: 56 AAV CBr-7.4 835 WO2016065001 SEQ ID NO: 57 AAV CBr-7.5 836 WO2016065001 SEQ ID NO: 58 AAV CBr-7.7 837 WO2016065001 SEQ ID NO: 59 AAV CBr-7.8 838 WO2016065001 SEQ ID NO: 60 AAV CBr-7.10 839 WO2016065001 SEQ ID NO: 61 AAV CKd-N3 840 WO2016065001 SEQ ID NO: 62 AAV CKd-N4 841 WO2016065001 SEQ ID NO: 63 AAV CKd-N9 842 WO2016065001 SEQ ID NO: 64 AAV CLv-L4 843 WO2016065001 SEQ ID NO: 65 AAV CLv-L5 844 WO2016065001 SEQ ID NO: 66 AAV CLv-L6 845 WO2016065001 SEQ ID NO: 67 AAV CLv-K1 846 WO2016065001 SEQ ID NO: 68 AAV CLv-K3 847 WO2016065001 SEQ ID NO: 69 AAV CLv-K6 848 WO2016065001 SEQ ID NO: 70 AAV CLv-M1 849 WO2016065001 SEQ ID NO: 71 AAV CLv-M11 850 WO2016065001 SEQ ID NO: 72 AAV CLv-M2 851 WO2016065001 SEQ ID NO: 73 AAV CLv-M5 852 WO2016065001 SEQ ID NO: 74 AAV CLv-M6 853 WO2016065001 SEQ ID NO: 75 AAV CLv-M7 854 WO2016065001 SEQ ID NO: 76 AAV CLv-M8 855 WO2016065001 SEQ ID NO: 77 AAV CLv-M9 856 WO2016065001 SEQ ID NO: 78 AAV CHt-P1 857 WO2016065001 SEQ ID NO: 79 AAV CHt-P6 858 WO2016065001 SEQ ID NO: 80 AAV CHt-P8 859 WO2016065001 SEQ ID NO: 81 AAV CHt-6.1 860 WO2016065001 SEQ ID NO: 82 AAV CHt-6.10 861 WO2016065001 SEQ ID NO: 83 AAV CHt-6.5 862 WO2016065001 SEQ ID NO: 84 AAV CHt-6.6 863 WO2016065001 SEQ ID NO: 85 AAV CHt-6.7 864 WO2016065001 SEQ ID NO: 86 AAV CHt-6.8 865 WO2016065001 SEQ ID NO: 87 AAV CSp-8.10 866 WO2016065001 SEQ ID NO: 88 AAV CSp-8.2 867 WO2016065001 SEQ ID NO: 89 AAV CSp-8.4 868 WO2016065001 SEQ ID NO: 90 AAV CSp-8.5 869 WO2016065001 SEQ ID NO: 91 AAV CSp-8.6 870 WO2016065001 SEQ ID NO: 92 AAV CSp-8.7 871 WO2016065001 SEQ ID NO: 93 AAV CSp-8.8 872 WO2016065001 SEQ ID NO: 94 AAV CSp-8.9 873 WO2016065001 SEQ ID NO: 95 AAV CBr-B7.3 874 WO2016065001 SEQ ID NO: 96 AAV CBr-B7.4 875 WO2016065001 SEQ ID NO: 97 AAV3B 876 WO2016065001 SEQ ID NO: 98 AAV4 877 WO2016065001 SEQ ID NO: 99 AAV5 878 WO2016065001 SEQ ID NO: 100 GPV 879 U.S. Pat. No. 9,624,274B2 SEQ ID NO: 192 B19 880 U.S. Pat. No. 9,624,274B2 SEQ ID NO: 193 MVM 881 U.S. Pat. No. 9,624,274B2 SEQ ID NO: 194 FPV 882 U.S. Pat. No. 9,624,274B2 SEQ ID NO: 195 CPV 883 U.S. Pat. No. 9,624,274B2 SEQ ID NO: 196 AAV6 884 U.S. Pat. No. 9,546,112B2 SEQ ID NO: 5 AAV6 885 U.S. Pat. No. 9,457,103B2 SEQ ID NO: 1 AAV2 886 U.S. Pat. No. 9,457,103B2 SEQ ID NO: 2 ShH10 887 U.S. Pat. No. 9,457,103B2 SEQ ID NO: 3 ShH13 888 U.S. Pat. No. 9,457,103B2 SEQ ID NO: 4 ShH10 889 U.S. Pat. No. 9,457,103B2 SEQ ID NO: 5 ShH10 890 U.S. Pat. No. 9,457,103B2 SEQ ID NO: 6 ShH10 891 U.S. Pat. No. 9,457,103B2 SEQ ID NO: 7 ShH10 892 U.S. Pat. No. 9,457,103B2 SEQ ID NO: 8 ShH10 893 U.S. Pat. No. 9,457,103B2 SEQ ID NO: 9 rh74 894 U.S. Pat. No. 9,434,928B2 SEQ ID NO: 1, US2015023924A1 SEQ ID NO: 2 rh74 895 U.S. Pat. No. 9,434,928B2 SEQ ID NO: 2, US2015023924A1 SEQ ID NO: 1 AAV8 896 U.S. Pat. No. 9,434,928B2 SEQ ID NO: 4 rh74 897 U.S. Pat. No. 9,434,928B2 SEQ ID NO: 5 rh74 (RHM4-1) 898 US2015023924A1 SEQ ID NO: 5, US20160375110A1 SEQ ID NO: 4 rh74 (RHM15-1) 899 US2015023924A1 SEQ ID NO: 6, US20160375110A1 SEQ ID NO: 5 rh74 (RHM15-2) 900 US2015023924A1 SEQ ID NO: 7, US20160375110A1 SEQ ID NO: 6 rh74 (RHM15-3/RHM15-5) 901 US2015023924A1 SEQ ID NO: 8, US20160375110A1 SEQ ID NO: 7 rh74 (RHM15-4) 902 US2015023924A1 SEQ ID NO: 9, US20160375110A1 SEQ ID NO: 8 rh74 (RHM15-6) 903 US2015023924A1 SEQ ID NO: 10, US20160375110A1 SEQ ID NO: 9 rh74 (RHM4-1) 904 US2015023924A1 SEQ ID NO: 11 rh74 (RHM15-1) 905 US2015023924A1 SEQ ID NO: 12 rh74 (RHM15-2) 906 US2015023924A1 SEQ ID NO: 13 rh74 (RHM15-3/RHM15-5) 907 US2015023924A1 SEQ ID NO: 14 rh74 (RHM15-4) 908 US2015023924A1 SEQ ID NO: 15 rh74 (RHM15-6) 909 US2015023924A1 SEQ ID NO: 16 AAV2 (comprising lung 910 US20160175389A1 SEQ ID NO: 9 specific polypeptide) AAV2 (comprising lung 911 US20160175389A1 SEQ ID NO: 10 specific polypeptide) Anc80 912 US20170051257A1 SEQ ID NO: 1 Anc80 913 US20170051257A1 SEQ ID NO: 2 Anc81 914 US20170051257A1 SEQ ID NO: 3 Anc80 915 US20170051257A1 SEQ ID NO: 4 Anc82 916 US20170051257A1 SEQ ID NO: 5 Anc82 917 US20170051257A1 SEQ ID NO: 6 Anc83 918 US20170051257A1 SEQ ID NO: 7 Anc83 919 US20170051257A1 SEQ ID NO: 8 Anc84 920 US20170051257A1 SEQ ID NO: 9 Anc84 921 US20170051257A1 SEQ ID NO: 10 Anc94 922 US20170051257A1 SEQ ID NO: 11 Anc94 923 US20170051257A1 SEQ ID NO: 12 Anc113 924 US20170051257A1 SEQ ID NO: 13 Anc113 925 US20170051257A1 SEQ ID NO: 14 Anc126 926 US20170051257A1 SEQ ID NO: 15 Anc126 927 US20170051257A1 SEQ ID NO: 16 Anc127 928 US20170051257A1 SEQ ID NO: 17 Anc127 929 US20170051257A1 SEQ ID NO: 18 Anc80L27 930 US20170051257A1 SEQ ID NO: 19 Anc80L59 931 US20170051257A1 SEQ ID NO: 20 Anc80L60 932 US20170051257A1 SEQ ID NO: 21 Anc80L62 933 US20170051257A1 SEQ ID NO: 22 Anc80L65 934 US20170051257A1 SEQ ID NO: 23 Anc80L33 935 US20170051257A1 SEQ ID NO: 24 Anc80L36 936 US20170051257A1 SEQ ID NO: 25 Anc80L44 937 US20170051257A1 SEQ ID NO: 26 Anc80L1 938 US20170051257A1 SEQ ID NO: 35 Anc80L1 939 US20170051257A1 SEQ ID NO: 36 AAV-X1 940 U.S. Pat. No. 8,283,151B2 SEQ ID NO: 11 AAV-X1b 941 U.S. Pat. No. 8,283,151B2 SEQ ID NO: 12 AAV-X5 942 U.S. Pat. No. 8,283,151B2 SEQ ID NO: 13 AAV-X19 943 U.S. Pat. No. 8,283,151B2 SEQ ID NO: 14 AAV-X21 944 U.S. Pat. No. 8,283,151B2 SEQ ID NO: 15 AAV-X22 945 U.S. Pat. No. 8,283,151B2 SEQ ID NO: 16 AAV-X23 946 U.S. Pat. No. 8,283,151B2 SEQ ID NO: 17 AAV-X24 947 U.S. Pat. No. 8,283,151B2 SEQ ID NO: 18 AAV-X25 948 U.S. Pat. No. 8,283,151B2 SEQ ID NO: 19 AAV-X26 949 U.S. Pat. No. 8,283,151B2 SEQ ID NO: 20 AAV-X1 950 U.S. Pat. No. 8,283,151B2 SEQ ID NO: 21 AAV-X1b 951 U.S. Pat. No. 8,283,151B2 SEQ ID NO: 22 AAV-X5 952 U.S. Pat. No. 8,283,151B2 SEQ ID NO: 23 AAV-X19 953 U.S. Pat. No. 8,283,151B2 SEQ ID NO: 24 AAV-X21 954 U.S. Pat. No. 8,283,151B2 SEQ ID NO: 25 AAV-X22 955 U.S. Pat. No. 8,283,151B2 SEQ ID NO: 26 AAV-X23 956 U.S. Pat. No. 8,283,151B2 SEQ ID NO: 27 AAV-X24 957 U.S. Pat. No. 8,283,151B2 SEQ ID NO: 28 AAV-X25 958 U.S. Pat. No. 8,283,151B2 SEQ ID NO: 29 AAV-X26 959 U.S. Pat. No. 8,283,151B2 SEQ ID NO: 30 AAVrh8 960 WO2016054554A1 SEQ ID NO: 8 AAVrh8VP2FC5 961 WO2016054554A1 SEQ ID NO: 9 AAVrh8VP2FC44 962 WO2016054554A1 SEQ ID NO: 10 AAVrh8VP2ApoB100 963 WO2016054554A1 SEQ ID NO: 11 AAVrh8VP2RVG 964 WO2016054554A1 SEQ ID NO: 12 AAVrh8VP2Angiopep-2 VP2 965 WO2016054554A1 SEQ ID NO: 13 AAV9.47VP1.3 966 WO2016054554A1 SEQ ID NO: 14 AAV9.47VP2ICAMg3 967 WO2016054554A1 SEQ ID NO: 15 AAV9.47VP2RVG 968 WO2016054554A1 SEQ ID NO: 16 AAV9.47VP2Angiopep-2 969 WO2016054554A1 SEQ ID NO: 17 AAV9.47VP2A-string 970 WO2016054554A1 SEQ ID NO: 18 AAVrh8VP2FC5 VP2 971 WO2016054554A1 SEQ ID NO: 19 AAVrh8VP2FC44 VP2 972 WO2016054554A1 SEQ ID NO: 20 AAVrh8VP2ApoB100 VP2 973 WO2016054554A1 SEQ ID NO: 21 AAVrh8VP2RVG VP2 974 WO2016054554A1 SEQ ID NO: 22 AAVrh8VP2Angiopep-2 VP2 975 WO2016054554A1 SEQ ID NO: 23 AAV9.47VP2ICAMg3 VP2 976 WO2016054554A1 SEQ ID NO: 24 AAV9.47VP2RVG VP2 977 WO2016054554A1 SEQ ID NO: 25 AAV9.47VP2Angiopep-2 VP2 978 WO2016054554A1 SEQ ID NO: 26 AAV9.47VP2A-string VP2 979 WO2016054554A1 SEQ ID NO: 27 rAAV-B1 980 WO2016054557A1 SEQ ID NO: 1 rAAV-B2 981 WO2016054557A1 SEQ ID NO: 2 rAAV-B3 982 WO2016054557A1 SEQ ID NO: 3 rAAV-B4 983 WO2016054557A1 SEQ ID NO: 4 rAAV-B1 984 WO2016054557A1 SEQ ID NO: 5 rAAV-B2 985 WO2016054557A1 SEQ ID NO: 6 rAAV-B3 986 WO2016054557A1 SEQ ID NO: 7 rAAV-B4 987 WO2016054557A1 SEQ ID NO: 8 rAAV-L1 988 WO2016054557A1 SEQ ID NO: 9 rAAV-L2 989 WO2016054557A1 SEQ ID NO: 10 rAAV-L3 990 WO2016054557A1 SEQ ID NO: 11 rAAV-L4 991 WO2016054557A1 SEQ ID NO: 12 rAAV-L1 992 WO2016054557A1 SEQ ID NO: 13 rAAV-L2 993 WO2016054557A1 SEQ ID NO: 14 rAAV-L3 994 WO2016054557A1 SEQ ID NO: 15 rAAV-L4 995 WO2016054557A1 SEQ ID NO: 16 AAV9 996 WO2016073739A1 SEQ ID NO: 3 rAAV 997 WO2016081811A1 SEQ ID NO: 1 rAAV 998 WO2016081811A1 SEQ ID NO: 2 rAAV 999 WO2016081811A1 SEQ ID NO: 3 rAAV 1000 WO2016081811A1 SEQ ID NO: 4 rAAV 1001 WO2016081811A1 SEQ ID NO: 5 rAAV 1002 WO2016081811A1 SEQ ID NO: 6 rAAV 1003 WO2016081811A1 SEQ ID NO: 7 rAAV 1004 WO2016081811A1 SEQ ID NO: 8 rAAV 1005 WO2016081811A1 SEQ ID NO: 9 rAAV 1006 WO2016081811A1 SEQ ID NO: 10 rAAV 1007 WO2016081811A1 SEQ ID NO: 11 rAAV 1008 WO2016081811A1 SEQ ID NO: 12 rAAV 1009 WO2016081811A1 SEQ ID NO: 13 rAAV 1010 WO2016081811A1 SEQ ID NO: 14 rAAV 1011 WO2016081811A1 SEQ ID NO: 15 rAAV 1012 WO2016081811A1 SEQ ID NO: 16 rAAV 1013 WO2016081811A1 SEQ ID NO: 17 rAAV 1014 WO2016081811A1 SEQ ID NO: 18 rAAV 1015 WO2016081811A1 SEQ ID NO: 19 rAAV 1016 WO2016081811A1 SEQ ID NO: 20 rAAV 1017 WO2016081811A1 SEQ ID NO: 21 rAAV 1018 WO2016081811A1 SEQ ID NO: 22 rAAV 1019 WO2016081811A1 SEQ ID NO: 23 rAAV 1020 WO2016081811A1 SEQ ID NO: 24 rAAV 1021 WO2016081811A1 SEQ ID NO: 25 rAAV 1022 WO2016081811A1 SEQ ID NO: 26 rAAV 1023 WO2016081811A1 SEQ ID NO: 27 rAAV 1024 WO2016081811A1 SEQ ID NO: 28 rAAV 1025 WO2016081811A1 SEQ ID NO: 29 rAAV 1026 WO2016081811A1 SEQ ID NO: 30 rAAV 1027 WO2016081811A1 SEQ ID NO: 31 rAAV 1028 WO2016081811A1 SEQ ID NO: 32 rAAV 1029 WO2016081811A1 SEQ ID NO: 33 rAAV 1030 WO2016081811A1 SEQ ID NO: 34 rAAV 1031 WO2016081811A1 SEQ ID NO: 35 rAAV 1032 WO2016081811A1 SEQ ID NO: 36 rAAV 1033 WO2016081811A1 SEQ ID NO: 37 rAAV 1034 WO2016081811A1 SEQ ID NO: 38 rAAV 1035 WO2016081811A1 SEQ ID NO: 39 rAAV 1036 WO2016081811A1 SEQ ID NO: 40 rAAV 1037 WO2016081811A1 SEQ ID NO: 41 rAAV 1038 WO2016081811A1 SEQ ID NO: 42 rAAV 1039 WO2016081811A1 SEQ ID NO: 43 rAAV 1040 WO2016081811A1 SEQ ID NO: 44 rAAV 1041 WO2016081811A1 SEQ ID NO: 45 rAAV 1042 WO2016081811A1 SEQ ID NO: 46 rAAV 1043 WO2016081811A1 SEQ ID NO: 47 rAAV 1044 WO2016081811A1 SEQ ID NO: 48 rAAV 1045 WO2016081811A1 SEQ ID NO: 49 rAAV 1046 WO2016081811A1 SEQ ID NO: 50 rAAV 1047 WO2016081811A1 SEQ ID NO: 51 rAAV 1048 WO2016081811A1 SEQ ID NO: 52 rAAV 1049 WO2016081811A1 SEQ ID NO: 53 rAAV 1050 WO2016081811A1 SEQ ID NO: 54 rAAV 1051 WO2016081811A1 SEQ ID NO: 55 rAAV 1052 WO2016081811A1 SEQ ID NO: 56 rAAV 1053 WO2016081811A1 SEQ ID NO: 57 rAAV 1054 WO2016081811A1 SEQ ID NO: 58 rAAV 1055 WO2016081811A1 SEQ ID NO: 59 rAAV 1056 WO2016081811A1 SEQ ID NO: 60 rAAV 1057 WO2016081811A1 SEQ ID NO: 61 rAAV 1058 WO2016081811A1 SEQ ID NO: 62 rAAV 1059 WO2016081811A1 SEQ ID NO: 63 rAAV 1060 WO2016081811A1 SEQ ID NO: 64 rAAV 1061 WO2016081811A1 SEQ ID NO: 65 rAAV 1062 WO2016081811A1 SEQ ID NO: 66 rAAV 1063 WO2016081811A1 SEQ ID NO: 67 rAAV 1064 WO2016081811A1 SEQ ID NO: 68 rAAV 1065 WO2016081811A1 SEQ ID NO: 69 rAAV 1066 WO2016081811A1 SEQ ID NO: 70 rAAV 1067 WO2016081811A1 SEQ ID NO: 71 rAAV 1068 WO2016081811A1 SEQ ID NO: 72 rAAV 1069 WO2016081811A1 SEQ ID NO: 73 rAAV 1070 WO2016081811A1 SEQ ID NO: 74 rAAV 1071 WO2016081811A1 SEQ ID NO: 75 rAAV 1072 WO2016081811A1 SEQ ID NO: 76 rAAV 1073 WO2016081811A1 SEQ ID NO: 77 rAAV 1074 WO2016081811A1 SEQ ID NO: 78 rAAV 1075 WO2016081811A1 SEQ ID NO: 79 rAAV 1076 WO2016081811A1 SEQ ID NO: 80 rAAV 1077 WO2016081811A1 SEQ ID NO: 81 rAAV 1078 WO2016081811A1 SEQ ID NO: 82 rAAV 1079 WO2016081811A1 SEQ ID NO: 83 rAAV 1080 WO2016081811A1 SEQ ID NO: 84 rAAV 1081 WO2016081811A1 SEQ ID NO: 85 rAAV 1082 WO2016081811A1 SEQ ID NO: 86 rAAV 1083 WO2016081811A1 SEQ ID NO: 87 rAAV 1084 WO2016081811A1 SEQ ID NO: 88 rAAV 1085 WO2016081811A1 SEQ ID NO: 89 rAAV 1086 WO2016081811A1 SEQ ID NO: 90 rAAV 1087 WO2016081811A1 SEQ ID NO: 91 rAAV 1088 WO2016081811A1 SEQ ID NO: 92 rAAV 1089 WO2016081811A1 SEQ ID NO: 93 rAAV 1090 WO2016081811A1 SEQ ID NO: 94 rAAV 1091 WO2016081811A1 SEQ ID NO: 95 rAAV 1092 WO2016081811A1 SEQ ID NO: 96 rAAV 1093 WO2016081811A1 SEQ ID NO: 97 rAAV 1094 WO2016081811A1 SEQ ID NO: 98 rAAV 1095 WO2016081811A1 SEQ ID NO: 99 rAAV 1096 WO2016081811A1 SEQ ID NO: 100 rAAV 1097 WO2016081811A1 SEQ ID NO: 101 rAAV 1098 WO2016081811A1 SEQ ID NO: 102 rAAV 1099 WO2016081811A1 SEQ ID NO: 103 rAAV 1100 WO2016081811A1 SEQ ID NO: 104 rAAV 1101 WO2016081811A1 SEQ ID NO: 105 rAAV 1102 WO2016081811A1 SEQ ID NO: 106 rAAV 1103 WO2016081811A1 SEQ ID NO: 107 rAAV 1104 WO2016081811A1 SEQ ID NO: 108 rAAV 1105 WO2016081811A1 SEQ ID NO: 109 rAAV 1106 WO2016081811A1 SEQ ID NO: 110 rAAV 1107 WO2016081811A1 SEQ ID NO: 111 rAAV 1108 WO2016081811A1 SEQ ID NO: 112 rAAV 1109 WO2016081811A1 SEQ ID NO: 113 rAAV 1110 WO2016081811A1 SEQ ID NO: 114 rAAV 1111 WO2016081811A1 SEQ ID NO: 115 rAAV 1112 WO2016081811A1 SEQ ID NO: 116 rAAV 1113 WO2016081811A1 SEQ ID NO: 117 rAAV 1114 WO2016081811A1 SEQ ID NO: 118 rAAV 1115 WO2016081811A1 SEQ ID NO: 119 rAAV 1116 WO2016081811A1 SEQ ID NO: 120 rAAV 1117 WO2016081811A1 SEQ ID NO: 121 rAAV 1118 WO2016081811A1 SEQ ID NO: 122 rAAV 1119 WO2016081811A1 SEQ ID NO: 123 rAAV 1120 WO2016081811A1 SEQ ID NO: 124 rAAV 1121 WO2016081811A1 SEQ ID NO: 125 rAAV 1122 WO2016081811A1 SEQ ID NO: 126 rAAV 1123 WO2016081811A1 SEQ ID NO: 127 rAAV 1124 WO2016081811A1 SEQ ID NO: 128 AAV8 E532K 1125 WO2016081811A1 SEQ ID NO: 133 AAV8 E532K 1126 WO2016081811A1 SEQ ID NO: 134 rAAV4 1127 WO2016115382A1 SEQ ID NO: 2 rAAV4 1128 WO2016115382A1 SEQ ID NO: 3 rAAV4 1129 WO2016115382A1 SEQ ID NO: 4 rAAV4 1130 WO2016115382A1 SEQ ID NO: 5 rAAV4 1131 WO2016115382A1 SEQ ID NO: 6 rAAV4 1132 WO2016115382A1 SEQ ID NO: 7 rAAV4 1133 WO2016115382A1 SEQ ID NO: 8 rAAV4 1134 WO2016115382A1 SEQ ID NO: 9 rAAV4 1135 WO2016115382A1 SEQ ID NO: 10 rAAV4 1136 WO2016115382A1 SEQ ID NO: 11 rAAV4 1137 WO2016115382A1 SEQ ID NO: 12 rAAV4 1138 WO2016115382A1 SEQ ID NO: 13 rAAV4 1139 WO2016115382A1 SEQ ID NO: 14 rAAV4 1140 WO2016115382A1 SEQ ID NO: 15 rAAV4 1141 WO2016115382A1 SEQ ID NO: 16 rAAV4 1142 WO2016115382A1 SEQ ID NO: 17 rAAV4 1143 WO2016115382A1 SEQ ID NO: 18 rAAV4 1144 WO2016115382A1 SEQ ID NO: 19 rAAV4 1145 WO2016115382A1 SEQ ID NO: 20 rAAV4 1146 WO2016115382A1 SEQ ID NO: 21 AAV11 1147 WO2016115382A1 SEQ ID NO: 22 AAV12 1148 WO2016115382A1 SEQ ID NO: 23 rh32 1149 WO2016115382A1 SEQ ID NO: 25 rh33 1150 WO2016115382A1 SEQ ID NO: 26 rh34 1151 WO2016115382A1 SEQ ID NO: 27 rAAV4 1152 WO2016115382A1 SEQ ID NO: 28 rAAV4 1153 WO2016115382A1 SEQ ID NO: 29 rAAV4 1154 WO2016115382A1 SEQ ID NO: 30 rAAV4 1155 WO2016115382A1 SEQ ID NO: 31 rAAV4 1156 WO2016115382A1 SEQ ID NO: 32 rAAV4 1157 WO2016115382A1 SEQ ID NO: 33 AAV2/8 1158 WO2016131981A1 SEQ ID NO: 47 AAV2/8 1159 WO2016131981A1 SEQ ID NO: 48 ancestral AAV 1160 WO2016154344A1 SEQ ID NO: 7 ancestral AAV variant C4 1161 WO2016154344A1 SEQ ID NO: 13 ancestral AAV variant C7 1162 WO2016154344A1 SEQ ID NO: 14 ancestral AAV variant G4 1163 WO2016154344A1 SEQ ID NO: 15 consensus amino acid sequence 1164 WO2016154344A1 SEQ ID NO: 16 of ancestral AAV variants, C4, C7 and G4 consensus amino acid sequence 1165 WO2016154344A1 SEQ ID NO: 17 of ancestral AAV variants, C4 and C7 AAV8 (with a AAV2 1166 WO2016150403A1 SEQ ID NO: 13 phospholipase domain) AAV VR-942n 1167 US20160289275A1 SEQ ID NO: 10 AAV5-A (M569V) 1168 US20160289275A1 SEQ ID NO: 13 AAV5-A (M569V) 1169 US20160289275A1 SEQ ID NO: 14 AAV5-A (Y585V) 1170 US20160289275A1 SEQ ID NO: 16 AAV5-A (Y585V) 1171 US20160289275A1 SEQ ID NO: 17 AAV5-A (L587T) 1172 US20160289275A1 SEQ ID NO: 19 AAV5-A (L587T) 1173 US20160289275A1 SEQ ID NO: 20 AAV5-A (Y585V/L587T) 1174 US20160289275A1 SEQ ID NO: 22 AAV5-A (Y585V7L587T) 1175 US20160289275A1 SEQ ID NO: 23 AAV5-B (D652A) 1176 US20160289275A1 SEQ ID NO: 25 AAV5-B (D652A) 1177 US20160289275A1 SEQ ID NO: 26 AAV5-B (T362M) 1178 US20160289275A1 SEQ ID NO: 28 AAV5-B (T362M) 1179 US20160289275A1 SEQ ID NO: 29 AAV5-B (Q359D) 1180 US20160289275A1 SEQ ID NO: 31 AAV5-B (Q359D) 1181 US20160289275A1 SEQ ID NO: 32 AAV5-B (E350Q) 1182 US20160289275A1 SEQ ID NO: 34 AAV5-B (E350Q) 1183 US20160289275A1 SEQ ID NO: 35 AAV5-B (P533S) 1184 US20160289275A1 SEQ ID NO: 37 AAV5-B (P533S) 1185 US20160289275A1 SEQ ID NO: 38 AAV5-B (P533G) 1186 US20160289275A1 SEQ ID NO: 40 AAV5-B (P533G) 1187 US20160289275A1 SEQ ID NO: 41 AAV5-mutation in loop VII 1188 US20160289275A1 SEQ ID NO: 43 AAV5 -mutation in loop VII 1189 US20160289275A1 SEQ ID NO: 44 AAV8 1190 US20160289275A1 SEQ ID NO: 47 Mut A (LK03/AAV8) 1191 WO2016181123A1 SEQ ID NO: 1 Mut B (LK03/AAV5) 1192 WO2016181123A1 SEQ ID NO: 2 Mut C (AAV8/AAV3B) 1193 WO2016181123A1 SEQ ID NO: 3 Mut D (AAV5/AAV3B) 1194 WO2016181123A1 SEQ ID NO: 4 Mut E (AAV8/AAV3B) 1195 WO2016181123A1 SEQ ID NO: 5 Mut F (AAV3B/AAV8) 1196 WO2016181123A1 SEQ ID NO: 6 AAV44.9 1197 WO2016183297A1 SEQ ID NO: 4 AAV44.9 1198 WO2016183297A1 SEQ ID NO: 5 AAVrh8 1199 WO2016183297A1 SEQ ID NO: 6 AAV44.9 (S470N) 1200 WO2016183297A1 SEQ ID NO: 9 rh74 VP1 1201 US20160375110A1 SEQ ID NO: 1 AAV-LK03 (L125I) 1202 WO2017015102A1 SEQ ID NO: 5 AAV3B (S663V + T492V) 1203 WO2017015102A1 SEQ ID NO: 6 Anc80 1204 WO2017019994A2 SEQ ID NO: 1 Anc80 1205 WO2017019994A2 SEQ ID NO: 2 Anc81 1206 WO2017019994A2 SEQ ID NO: 3 Anc81 1207 WO2017019994A2 SEQ ID NO: 4 Anc82 1208 WO2017019994A2 SEQ ID NO: 5 Anc82 1209 WO2017019994A2 SEQ ID NO: 6 Anc83 1210 WO2017019994A2 SEQ ID NO: 7 Anc83 1211 WO2017019994A2 SEQ ID NO: 8 Anc84 1212 WO2017019994A2 SEQ ID NO: 9 Anc84 1213 WO2017019994A2 SEQ ID NO: 10 Anc94 1214 WO2017019994A2 SEQ ID NO: 11 Anc94 1215 WO2017019994A2 SEQ ID NO: 12 Anc113 1216 WO2017019994A2 SEQ ID NO: 13 Anc13 1217 WO2017019994A2 SEQ ID NO: 14 Anc126 1218 WO2017019994A2 SEQ ID NO: 15 Anc126 1219 WO2017019994A2 SEQ ID NO: 16 Anc127 1220 WO2017019994A2 SEQ ID NO: 17 Anc127 1221 WO2017019994A2 SEQ ID NO: 18 Anc80L27 1222 WO2017019994A2 SEQ ID NO: 19 Anc80L59 1223 WO2017019994A2 SEQ ID NO: 20 Anc80L60 1224 WO2017019994A2 SEQ ID NO: 21 Anc80L62 1225 WO2017019994A2 SEQ ID NO: 22 Anc80L65 1226 WO2017019994A2 SEQ ID NO: 23 Anc80L33 1227 WO2017019994A2 SEQ ID NO: 24 Anc80L36 1228 WO2017019994A2 SEQ ID NO: 25 Anc80L44 1229 WO2017019994A2 SEQ ID NO: 26 Anc80L1 1230 WO2017019994A2 SEQ ID NO: 35 Anc80L1 1231 WO2017019994A2 SEQ ID NO: 36 AAVrh10 1232 WO2017019994A2 SEQ ID NO: 41 Anc110 1233 WO2017019994A2 SEQ ID NO: 42 Anc110 1234 WO2017019994A2 SEQ ID NO: 43 AAVrh32.33 1235 WO2017019994A2 SEQ ID NO: 45 AAVrh74 1236 WO2017049031A1 SEQ ID NO: 1 AAV2 1237 WO2017053629A2 SEQ ID NO: 49 AAV2 1238 WO2017053629A2 SEQ ID NO: 50 AAV2 1239 WO2017053629A2 SEQ ID NO: 82 Parvo-like virus 1240 WO2017070476A2 SEQ ID NO: 1 Parvo-like virus 1241 WO2017070476A2 SEQ ID NO: 2 Parvo-like virus 1242 WO2017070476A2 SEQ ID NO: 3 Parvo-like virus 1243 WO2017070476A2 SEQ ID NO: 4 Parvo-like virus 1244 WO2017070476A2 SEQ ID NO: 5 Parvo-like virus 1245 WO2017070476A2 SEQ ID NO: 6 AAVrh.10 1246 WO2017070516A1 SEQ ID NO: 7 AAVrh.10 1247 WO2017070516A1 SEQ ID NO: 14 AAV2tYF 1248 WO2017070491A1 SEQ ID NO: 1 AAV-SPK 1249 WO2017075619A1 SEQ ID NO: 28 AAV2.5 1250 US20170128528A1 SEQ ID NO: 13 AAV1.1 1251 US20170128528A1 SEQ ID NO: 15 AAV6.1 1252 US20170128528A1 SEQ ID NO: 17 AAV6.3.1 1253 US20170128528A1 SEQ ID NO: 18 AAV2i8 1254 US20170128528A1 SEQ ID NO: 28 AAV2i8 1255 US20170128528A1 SEQ ID NO: 29 ttAAV 1256 US20170128528A1 SEQ ID NO: 30 ttAAV-S312N 1257 US20170128528A1 SEQ ID NO: 32 ttAAV-S312N 1258 US20170128528A1 SEQ ID NO: 33 AAV6 (Y705, Y731, and T492) 1259 WO2016134337A1 SEQ ID NO: 24 AAV2 1260 WO2016134375A1 SEQ ID NO: 9 AAV2 1261 WO2016134375A1 SEQ ID NO: 10 AAV2 variant 2322 WO2018071831 SEQ ID NO: 1 AAV2 variant 2323 WO2018071831 SEQ ID NO: 2 AAV2 variant 2324 WO2018071831 SEQ ID NO: 3 AAV2 variant 2325 WO2018071831 SEQ ID NO: 4 AAV2 variant 2326 WO2018071831 SEQ ID NO: 5 AAV2 variant 2327 WO2018071831 SEQ ID NO: 6 AAV2 variant 2328 WO2018071831 SEQ ID NO: 7 AAV2 variant 2329 WO2018071831 SEQ ID NO: 8 AAV2 variant 2330 WO2018071831 SEQ ID NO: 9 AAV2 variant 2331 WO2018071831 SEQ ID NO: 10 AAV2 variant 2332 WO2018071831 SEQ ID NO: 11 AAV2 variant 2333 WO2018071831 SEQ ID NO: 12 AAV2 variant 2334 WO2018071831 SEQ ID NO: 13 AAV2 variant 2335 WO2018071831 SEQ ID NO: 14 AAV2 variant 2336 WO2018071831 SEQ ID NO: 15 AAV2 variant 2337 WO2018071831 SEQ ID NO: 16 AAV2 variant 2338 WO2018071831 SEQ ID NO: 17 AAV2 variant 2339 WO2018071831 SEQ ID NO: 18 AAV2 variant 2340 WO2018071831 SEQ ID NO: 19 AAV2 variant 2341 WO2018071831 SEQ ID NO: 20 AAV2 variant 2342 WO2018071831 SEQ ID NO: 21 AAV2 variant 2343 WO2018071831 SEQ ID NO: 22 AAV2 variant 2344 WO2018071831 SEQ ID NO: 23 AAV2 variant 2345 WO2018071831 SEQ ID NO: 24 AAV2 variant 2346 WO2018071831 SEQ ID NO: 25 AAV2 variant 2347 WO2018071831 SEQ ID NO: 26 AAV2 variant 2348 WO2018071831 SEQ ID NO: 27 AAV2 variant 2349 WO2018071831 SEQ ID NO: 28 AAV2 variant 2350 WO2018071831 SEQ ID NO: 29 AAV2 variant 2351 WO2018071831 SEQ ID NO: 30 AAV2 variant 2352 WO2018071831 SEQ ID NO: 31 AAV2 variant 2353 WO2018071831 SEQ ID NO: 32 AAV2 variant 2354 WO2018071831 SEQ ID NO: 33 AAV2 variant 2355 WO2018071831 SEQ ID NO: 34 AAV2 variant 2356 WO2018071831 SEQ ID NO: 35 AAV2 variant 2357 WO2018071831 SEQ ID NO: 36 AAV2 variant 2358 WO2018071831 SEQ ID NO: 37 AAV2 variant 2359 WO2018071831 SEQ ID NO: 38 AAV2 variant 2360 WO2018071831 SEQ ID NO: 39 AAV2 variant 2361 WO2018071831 SEQ ID NO: 40 AAV2 variant 2362 WO2018071831 SEQ ID NO: 41 AAV2 variant 2363 WO2018071831 SEQ ID NO: 42 AAV2 variant 2364 WO2018071831 SEQ ID NO: 43 AAV2 variant 2365 WO2018071831 SEQ ID NO: 44 AAV2 variant 2366 WO2018071831 SEQ ID NO: 45 AAV2 variant 2367 WO2018071831 SEQ ID NO: 46 AAV2 variant 2368 WO2018071831 SEQ ID NO: 47 AAV2 variant 2369 WO2018071831 SEQ ID NO: 48 AAV2 variant 2370 WO2018071831 SEQ ID NO: 49 AAV2 variant 2371 WO2018071831 SEQ ID NO: 50 AAV2 variant 2372 WO2018071831 SEQ ID NO: 51 AAV2 variant 2373 WO2018071831 SEQ ID NO: 52 AAV2 variant 2374 WO2018071831 SEQ ID NO: 53 AAV2 variant 2375 WO2018071831 SEQ ID NO: 54 AAV2 variant 2376 WO2018071831 SEQ ID NO: 55 AAV2 variant 2377 WO2018071831 SEQ ID NO: 56 AAV2 variant 2378 WO2018071831 SEQ ID NO: 57 AAV2 variant 2379 WO2018071831 SEQ ID NO: 58 AAV2 variant 2380 WO2018071831 SEQ ID NO: 59 AAV2 variant 2381 WO2018071831 SEQ ID NO: 60 AAV2 variant 2382 WO2018071831 SEQ ID NO: 61 AAV2 variant 2383 WO2018071831 SEQ ID NO: 62 AAV2 variant 2384 WO2018071831 SEQ ID NO: 63 AAV2 variant 2385 WO2018071831 SEQ ID NO: 64 AAV2 variant 2386 WO2018071831 SEQ ID NO: 65 AAV2 variant 2387 WO2018071831 SEQ ID NO: 66 AAV2 variant 2388 WO2018071831 SEQ ID NO: 67 AAV2 variant 2389 WO2018071831 SEQ ID NO: 68 AAV2 variant 2390 WO2018071831 SEQ ID NO: 69 AAV2 variant 2391 WO2018071831 SEQ ID NO: 70 AAV2 variant 2392 WO2018071831 SEQ ID NO: 71 AAV2 variant 2393 WO2018071831 SEQ ID NO: 72 AAV2 variant 2394 WO2018071831 SEQ ID NO: 73 AAV2 variant 2395 WO2018071831 SEQ ID NO: 74 AAV2 variant 2396 WO2018071831 SEQ ID NO: 75 AAV2 variant 2397 WO2018071831 SEQ ID NO: 76 AAV2 variant 2398 WO2018071831 SEQ ID NO: 77 AAV2 variant 2399 WO2018071831 SEQ ID NO: 78 AAV2 variant 2400 WO2018071831 SEQ ID NO: 79 AAV2 variant 2401 WO2018071831 SEQ ID NO: 80 AAV2 variant 2402 WO2018071831 SEQ ID NO: 81 AAV2 variant 2403 WO2018071831 SEQ ID NO: 82 AAV2 variant 2404 WO2018071831 SEQ ID NO: 83 AAV2 variant 2405 WO2018071831 SEQ ID NO: 84 AAV2 variant 2406 WO2018071831 SEQ ID NO: 85 AAV2 variant 2407 WO2018071831 SEQ ID NO: 86 AAV2 variant 2408 WO2018071831 SEQ ID NO: 87 AAV2 variant 2409 WO2018071831 SEQ ID NO: 88 AAV2 variant 2410 WO2018071831 SEQ ID NO: 89 AAV2 variant 2411 WO2018071831 SEQ ID NO: 90 AAV2 variant 2412 WO2018071831 SEQ ID NO: 91 AAV2 variant 2413 WO2018071831 SEQ ID NO: 92 AAV2 variant 2414 WO2018071831 SEQ ID NO: 93 AAV2 variant 2415 WO2018071831 SEQ ID NO: 94 AAV2 variant 2416 WO2018071831 SEQ ID NO: 95 AAV2 variant 2417 WO2018071831 SEQ ID NO: 96 AAV2 variant 2418 WO2018071831 SEQ ID NO: 97 AAV2 variant 2419 WO2018071831 SEQ ID NO: 98 AAV2 variant 2420 WO2018071831 SEQ ID NO: 99 AAV2 variant 2421 WO2018071831 SEQ ID NO: 100 AAV2 variant 2422 WO2018071831 SEQ ID NO: 101 AAV2 variant 2423 WO2018071831 SEQ ID NO: 102 AAV2 variant 2424 WO2018071831 SEQ ID NO: 103 AAV2 variant 2425 WO2018071831 SEQ ID NO: 104 AAV2 variant 2426 WO2018071831 SEQ ID NO: 105 AAV2 variant 2427 WO2018071831 SEQ ID NO: 106 AAV2 variant 2428 WO2018071831 SEQ ID NO: 107 AAV2 variant 2429 WO2018071831 SEQ ID NO: 108 AAV2 variant 2430 WO2018071831 SEQ ID NO: 109 AAV2 variant 2431 WO2018071831 SEQ ID NO: 110 AAV2 variant 2432 WO2018071831 SEQ ID NO: 111 AAV2 variant 2433 WO2018071831 SEQ ID NO: 112 AAV2 variant 2434 WO2018071831 SEQ ID NO: 113 AAV2 variant 2435 WO2018071831 SEQ ID NO: 114 AAV2 variant 2436 WO2018071831 SEQ ID NO: 115 AAV2 variant 2437 WO2018071831 SEQ ID NO: 116 AAV2 variant 2438 WO2018071831 SEQ ID NO: 117 AAV2 variant 2439 WO2018071831 SEQ ID NO: 118 AAV2 variant 2440 WO2018071831 SEQ ID NO: 119 AAV2 variant 2441 WO2018071831 SEQ ID NO: 120 AAV2 variant 2442 WO2018071831 SEQ ID NO: 121 AAV2 variant 2443 WO2018071831 SEQ ID NO: 122 AAV2 variant 2444 WO2018071831 SEQ ID NO: 123 AAV2 variant 2445 WO2018071831 SEQ ID NO: 124 AAV2 variant 2446 WO2018071831 SEQ ID NO: 125 AAV2 variant 2447 WO2018071831 SEQ ID NO: 126 AAV2 variant 2448 WO2018071831 SEQ ID NO: 127 AAV2 variant 2449 WO2018071831 SEQ ID NO: 128 AAV2 variant 2450 WO2018071831 SEQ ID NO: 129 AAV2 variant 2451 WO2018071831 SEQ ID NO: 130 AAV2 variant 2452 WO2018071831 SEQ ID NO: 131 AAV2 variant 2453 WO2018071831 SEQ ID NO: 132 AAV2 variant 2454 WO2018071831 SEQ ID NO: 133 AAV2 variant 2455 WO2018071831 SEQ ID NO: 134 AAV2 variant 2456 WO2018071831 SEQ ID NO: 135 AAV2 variant 2457 WO2018071831 SEQ ID NO: 136 AAV2 variant 2458 WO2018071831 SEQ ID NO: 137 AAV2 variant 2459 WO2018071831 SEQ ID NO: 138 AAV2 variant 2460 WO2018071831 SEQ ID NO: 139 AAV2 variant 2461 WO2018071831 SEQ ID NO: 140 AAV2 variant 2462 WO2018071831 SEQ ID NO: 141 AAV2 variant 2463 WO2018071831 SEQ ID NO: 142 AAV2 variant 2464 WO2018071831 SEQ ID NO: 143 AAV2 variant 2465 WO2018071831 SEQ ID NO: 144 AAV2 variant 2466 WO2018071831 SEQ ID NO: 145 AAV2 variant 2467 WO2018071831 SEQ ID NO: 146 AAV2 variant 2468 WO2018071831 SEQ ID NO: 147 AAV2 variant 2469 WO2018071831 SEQ ID NO: 148 AAV2 variant 2470 WO2018071831 SEQ ID NO: 149 AAV2 variant 2471 WO2018071831 SEQ ID NO: 150 AAV2 variant 2472 WO2018071831 SEQ ID NO: 151 AAV2 variant 2473 WO2018071831 SEQ ID NO: 152 AAV2 variant 2474 WO2018071831 SEQ ID NO: 153 AAV2 variant 2475 WO2018071831 SEQ ID NO: 154 AAV2 variant 2476 WO2018071831 SEQ ID NO: 155 AAV2 variant 2477 WO2018071831 SEQ ID NO: 156 AAV2 variant 2478 WO2018071831 SEQ ID NO: 157 AAV2 variant 2479 WO2018071831 SEQ ID NO: 158 AAV2 variant 2480 WO2018071831 SEQ ID NO: 159 AAV2 variant 2481 WO2018071831 SEQ ID NO: 160 AAV2 variant 2482 WO2018071831 SEQ ID NO: 161 AAV2 variant 2483 WO2018071831 SEQ ID NO: 162 AAV2 variant 2484 WO2018071831 SEQ ID NO: 163 AAV2 variant 2485 WO2018071831 SEQ ID NO: 164 AAV2 variant 2486 WO2018071831 SEQ ID NO: 165 AAV2 variant 2487 WO2018071831 SEQ ID NO: 166 AAV2 variant 2488 WO2018071831 SEQ ID NO: 167 AAV2 variant 2489 WO2018071831 SEQ ID NO: 168 AAV2 variant 2490 WO2018071831 SEQ ID NO: 169 AAV2 variant 2491 WO2018071831 SEQ ID NO: 170 AAV2 variant 2492 WO2018071831 SEQ ID NO: 171 AAV2 variant 2493 WO2018071831 SEQ ID NO: 172 AAV2 variant 2494 WO2018071831 SEQ ID NO: 173 AAV2 variant 2495 WO2018071831 SEQ ID NO: 174 AAV2 variant 2496 WO2018071831 SEQ ID NO: 175 AAV2 variant 2497 WO2018071831 SEQ ID NO: 176 AAV2 variant 2498 WO2018071831 SEQ ID NO: 177 AAV2 variant 2499 WO2018071831 SEQ ID NO: 178 AAV2 variant 2500 WO2018071831 SEQ ID NO: 179 AAV2 variant 2501 WO2018071831 SEQ ID NO: 180 AAV2 variant 2502 WO2018071831 SEQ ID NO: 181 AAV2 variant 2503 WO2018071831 SEQ ID NO: 182 AAV2 variant 2504 WO2018071831 SEQ ID NO: 183 AAV2 variant 2505 WO2018071831 SEQ ID NO: 184 AAV2 variant 2506 WO2018071831 SEQ ID NO: 185 AAV2 variant 2507 WO2018071831 SEQ ID NO: 186 AAV2 variant 2508 WO2018071831 SEQ ID NO: 187 AAV2 variant 2509 WO2018071831 SEQ ID NO: 188 AAV2 variant 2510 WO2018071831 SEQ ID NO: 189 AAV2 variant 2511 WO2018071831 SEQ ID NO: 190 AAV2 variant 2512 WO2018071831 SEQ ID NO: 191 AAV2 variant 2513 WO2018071831 SEQ ID NO: 192 AAV2 variant 2514 WO2018071831 SEQ ID NO: 193 AAV2 variant 2515 WO2018071831 SEQ ID NO: 194 AAV2 variant 2516 WO2018071831 SEQ ID NO: 195 AAV2 variant 2517 WO2018071831 SEQ ID NO: 196 AAV2 variant 2518 WO2018071831 SEQ ID NO: 197 AAV2 variant 2519 WO2018071831 SEQ ID NO: 198 AAV2 variant 2520 WO2018071831 SEQ ID NO: 199 AAV2 variant 2521 WO2018071831 SEQ ID NO: 200 AAV2 variant 2522 WO2018071831 SEQ ID NO: 201 AAV2 variant 2523 WO2018071831 SEQ ID NO: 202 AAV2 variant 2524 WO2018071831 SEQ ID NO: 203 AAV2 variant 2525 WO2018071831 SEQ ID NO: 204 AAV2 variant 2526 WO2018071831 SEQ ID NO: 205 AAV2 variant 2527 WO2018071831 SEQ ID NO: 206 AAV2 variant 2528 WO2018071831 SEQ ID NO: 207 AAV2 variant 2529 WO2018071831 SEQ ID NO: 208 AAV2 variant 2530 WO2018071831 SEQ ID NO: 209 AAV2 variant 2531 WO2018071831 SEQ ID NO: 210 AAV2 variant 2532 WO2018071831 SEQ ID NO: 211 AAV2 variant 2533 WO2018071831 SEQ ID NO: 212 AAV2 variant 2534 WO2018071831 SEQ ID NO: 213 AAV2 variant 2535 WO2018071831 SEQ ID NO: 214 AAV2 variant 2536 WO2018071831 SEQ ID NO: 215 AAV2 variant 2537 WO2018071831 SEQ ID NO: 216 AAV2 variant 2538 WO2018071831 SEQ ID NO: 217 AAV2 variant 2539 WO2018071831 SEQ ID NO: 218 AAV2 variant 2540 WO2018071831 SEQ ID NO: 219 AAV2 variant 2541 WO2018071831 SEQ ID NO: 220 AAV2 variant 2542 WO2018071831 SEQ ID NO: 221 AAV2 variant 2543 WO2018071831 SEQ ID NO: 222 AAV2 variant 2544 WO2018071831 SEQ ID NO: 223 AAV2 variant 2545 WO2018071831 SEQ ID NO: 224 AAV2 variant 2546 WO2018071831 SEQ ID NO: 225 AAV2 variant 2547 WO2018071831 SEQ ID NO: 226 AAV2 variant 2548 WO2018071831 SEQ ID NO: 227 AAV2 variant 2549 WO2018071831 SEQ ID NO: 228 AAV2 variant 2550 WO2018071831 SEQ ID NO: 229 AAV2 variant 2551 WO2018071831 SEQ ID NO: 230 AAV2 variant 2552 WO2018071831 SEQ ID NO: 231 AAV2 variant 2553 WO2018071831 SEQ ID NO: 232 AAV2 variant 2554 WO2018071831 SEQ ID NO: 233 AAV2 variant 2555 WO2018071831 SEQ ID NO: 234 AAV2 variant 2556 WO2018071831 SEQ ID NO: 235 AAV2 variant 2557 WO2018071831 SEQ ID NO: 236 AAV2 variant 2558 WO2018071831 SEQ ID NO: 237 AAV2 variant 2559 WO2018071831 SEQ ID NO: 238 AAV2 variant 2560 WO2018071831 SEQ ID NO: 239 AAV2 variant 2561 WO2018071831 SEQ ID NO: 240 AAV2 variant 2562 WO2018071831 SEQ ID NO: 241 AAV2 variant 2563 WO2018071831 SEQ ID NO: 242 AAV2 variant 2564 WO2018071831 SEQ ID NO: 243 AAV2 variant 2565 WO2018071831 SEQ ID NO: 244 AAV2 variant 2566 WO2018071831 SEQ ID NO: 245 AAV2 variant 2567 WO2018071831 SEQ ID NO: 246 AAV2 variant 2568 WO2018071831 SEQ ID NO: 247 AAV2 variant 2569 WO2018071831 SEQ ID NO: 248 AAV2 variant 2570 WO2018071831 SEQ ID NO: 249 AAV2 variant 2571 WO2018071831 SEQ ID NO: 250 AAV2 variant 2572 WO2018071831 SEQ ID NO: 251 AAV2 variant 2573 WO2018071831 SEQ ID NO: 252 AAV2 variant 2574 WO2018071831 SEQ ID NO: 253 AAV2 variant 2575 WO2018071831 SEQ ID NO: 254 AAV2 variant 2576 WO2018071831 SEQ ID NO: 255 AAV2 variant 2577 WO2018071831 SEQ ID NO: 256 AAV2 variant 2578 WO2018071831 SEQ ID NO: 257 AAV2 variant 2579 WO2018071831 SEQ ID NO: 258 AAV2 variant 2580 WO2018071831 SEQ ID NO: 259 AAV2 variant 2584 WO2018071831 SEQ ID NO: 260 AAV2 variant 2582 WO2018071831 SEQ ID NO: 261 AAV2 variant 2583 WO2018071831 SEQ ID NO: 262 AAV2 variant 2584 WO2018071831 SEQ ID NO: 263 AAV2 variant 2585 WO2018071831 SEQ ID NO: 264 AAV2 variant 2586 WO2018071831 SEQ ID NO: 265 AAV2 variant 2587 WO2018071831 SEQ ID NO: 266 AAV2 variant 2588 WO2018071831 SEQ ID NO: 267 AAV2 variant 2589 WO2018071831 SEQ ID NO: 268 AAV2 variant 2590 WO2018071831 SEQ ID NO: 269 AAV2 variant 2591 WO2018071831 SEQ ID NO: 270 AAV2 variant 2592 WO2018071831 SEQ ID NO: 271 AAV2 variant 2593 WO2018071831 SEQ ID NO: 272 AAV2 variant 2594 WO2018071831 SEQ ID NO: 273 AAV2 variant 2595 WO2018071831 SEQ ID NO: 274 AAV2 variant 2596 WO2018071831 SEQ ID NO: 275 AAV2 variant 2597 WO2018071831 SEQ ID NO: 276 AAV2 variant 2598 WO2018071831 SEQ ID NO: 277 AAV2 variant 2599 WO2018071831 SEQ ID NO: 278 AAV2 variant 2600 WO2018071831 SEQ ID NO: 279 AAV2 variant 2601 WO2018071831 SEQ ID NO: 280 AAV2 variant 2602 WO2018071831 SEQ ID NO: 281 AAV2 variant 2603 WO2018071831 SEQ ID NO: 282 AAV2 variant 2604 WO2018071831 SEQ ID NO: 283 AAV2 variant 2605 WO2018071831 SEQ ID NO: 284 AAV2 variant 2606 WO2018071831 SEQ ID NO: 285 AAV2 variant 2607 WO2018071831 SEQ ID NO: 286 AAV2 variant 2608 WO2018071831 SEQ ID NO: 287 AAV2 variant 2609 WO2018071831 SEQ ID NO: 288 AAV2 variant 2610 WO2018071831 SEQ ID NO: 289 AAV2 variant 2611 WO2018071831 SEQ ID NO: 290 AAV2 variant 2612 WO2018071831 SEQ ID NO: 291 AAV2 variant 2613 WO2018071831 SEQ ID NO: 292 AAV2 variant 2614 WO2018071831 SEQ ID NO: 293 AAV2 variant 2615 WO2018071831 SEQ ID NO: 294 AAV2 variant 2616 WO2018071831 SEQ ID NO: 295 AAV2 variant 2617 WO2018071831 SEQ ID NO: 296 AAV2 variant 2618 WO2018071831 SEQ ID NO: 297 AAV2 variant 2619 WO2018071831 SEQ ID NO: 298 AAV2 variant 2620 WO2018071831 SEQ ID NO: 299 AAV2 variant 2621 WO2018071831 SEQ ID NO: 300 AAV2 variant 2622 WO2018071831 SEQ ID NO: 301 AAV2 variant 2623 WO2018071831 SEQ ID NO: 302 AAV2 variant 2624 WO2018071831 SEQ ID NO: 303 AAV2 variant 2625 WO2018071831 SEQ ID NO: 304 AAV2 variant 2626 WO2018071831 SEQ ID NO: 305 AAV2 variant 2627 WO2018071831 SEQ ID NO: 306 AAV2 variant 2628 WO2018071831 SEQ ID NO: 307 AAV2 variant 2629 WO2018071831 SEQ ID NO: 308 AAV2 variant 2630 WO2018071831 SEQ ID NO: 309 AAV2 variant 2631 WO2018071831 SEQ ID NO: 310 AAV2 variant 2632 WO2018071831 SEQ ID NO: 311 AAV2 variant 2633 WO2018071831 SEQ ID NO: 312 AAV2 variant 2634 WO2018071831 SEQ ID NO: 313 AAV2 variant 2635 WO2018071831 SEQ ID NO: 314 AAV2 variant 2636 WO2018071831 SEQ ID NO: 315 AAV2 variant 2637 WO2018071831 SEQ ID NO: 316 AAV2 variant 2638 WO2018071831 SEQ ID NO: 317 AAV2 variant 2639 WO2018071831 SEQ ID NO: 318 AAV2 variant 2640 WO2018071831 SEQ ID NO: 319 AAV2 variant 2641 WO2018071831 SEQ ID NO: 320 AAV2 variant 2642 WO2018071831 SEQ ID NO: 321 AAV2 variant 2643 WO2018071831 SEQ ID NO: 322 AAV2 variant 2644 WO2018071831 SEQ ID NO: 323 AAV2 variant 2645 WO2018071831 SEQ ID NO: 324 AAV2 variant 2646 WO2018071831 SEQ ID NO: 325 AAV2 variant 2647 WO2018071831 SEQ ID NO: 326 AAV2 variant 2648 WO2018071831 SEQ ID NO: 327 AAV2 variant 2649 WO2018071831 SEQ ID NO: 328 AAV2 variant 2650 WO2018071831 SEQ ID NO: 329 AAV2 variant 2651 WO2018071831 SEQ ID NO: 330 AAV2 variant 2652 WO2018071831 SEQ ID NO: 331 AAV2 variant 2653 WO2018071831 SEQ ID NO: 332 AAV2 variant 2654 WO2018071831 SEQ ID NO: 333 AAV2 variant 2655 WO2018071831 SEQ ID NO: 334 AAV2 variant 2656 WO2018071831 SEQ ID NO: 335 AAV2 variant 2657 WO2018071831 SEQ ID NO: 336 AAV2 variant 2658 WO2018071831 SEQ ID NO: 337 AAV2 variant 2659 WO2018071831 SEQ ID NO: 338 AAV2 variant 2660 WO2018071831 SEQ ID NO: 339 AAV2 variant 2661 WO2018071831 SEQ ID NO: 340 AAV2 variant 2662 WO2018071831 SEQ ID NO: 341 AAV2 variant 2663 WO2018071831 SEQ ID NO: 342 AAV2 variant 2664 WO2018071831 SEQ ID NO: 343 AAV2 variant 2665 WO2018071831 SEQ ID NO: 344 AAV2 variant 2666 WO2018071831 SEQ ID NO: 345 AAV2 variant 2667 WO2018071831 SEQ ID NO: 346 AAV2 variant 2668 WO2018071831 SEQ ID NO: 347 AAV2 variant 2669 WO2018071831 SEQ ID NO: 348 AAV2 variant 2670 WO2018071831 SEQ ID NO: 349 AAV2 variant 2671 WO2018071831 SEQ ID NO: 350 AAV2 variant 2672 WO2018071831 SEQ ID NO: 351 AAV2 variant 2673 WO2018071831 SEQ ID NO: 352 AAV2 variant 2674 WO2018071831 SEQ ID NO: 353 AAV2 variant 2675 WO2018071831 SEQ ID NO: 354 AAV2 variant 2676 WO2018071831 SEQ ID NO: 355 AAV2 variant 2677 WO2018071831 SEQ ID NO: 356 AAV2 variant 2678 WO2018071831 SEQ ID NO: 357 AAV2 variant 2679 WO2018071831 SEQ ID NO: 358 AAV2 variant 2680 WO2018071831 SEQ ID NO: 359 AAV2 variant 2681 WO2018071831 SEQ ID NO: 360 AAV2 variant 2682 WO2018071831 SEQ ID NO: 361 AAV2 variant 2683 WO2018071831 SEQ ID NO: 362 AAV2 variant 2684 WO2018071831 SEQ ID NO: 363 AAV2 variant 2685 WO2018071831 SEQ ID NO: 364 AAV2 variant 2686 WO2018071831 SEQ ID NO: 365 AAV2 variant 2687 WO2018071831 SEQ ID NO: 366 AAV2 variant 2688 WO2018071831 SEQ ID NO: 367 AAV2 variant 2689 WO2018071831 SEQ ID NO: 368 AAV2 variant 2690 WO2018071831 SEQ ID NO: 369 AAV2 variant 2691 WO2018071831 SEQ ID NO: 370 AAV2 variant 2692 WO2018071831 SEQ ID NO: 371 AAV2 variant 2693 WO2018071831 SEQ ID NO: 372 AAV2 variant 2694 WO2018071831 SEQ ID NO: 373 AAV2 variant 2695 WO2018071831 SEQ ID NO: 374 AAV2 variant 2696 WO2018071831 SEQ ID NO: 375 AAV2 variant 2697 WO2018071831 SEQ ID NO: 376 AAV2 variant 2698 WO2018071831 SEQ ID NO: 377 AAV2 variant 2699 WO2018071831 SEQ ID NO: 378 AAV2 variant 2700 WO2018071831 SEQ ID NO: 379 AAV2 variant 2701 WO2018071831 SEQ ID NO: 380 AAV2 variant 2702 WO2018071831 SEQ ID NO: 381 AAV2 variant 2703 WO2018071831 SEQ ID NO: 382 AAV2 variant 2704 WO2018071831 SEQ ID NO: 383 AAV2 variant 2705 WO2018071831 SEQ ID NO: 384 AAV2 variant 2706 WO2018071831 SEQ ID NO: 385 AAV2 variant 2707 WO2018071831 SEQ ID NO: 386 AAV2 variant 2708 WO2018071831 SEQ ID NO: 387 AAV2 variant 2709 WO2018071831 SEQ ID NO: 388 AAV2 variant 2710 WO2018071831 SEQ ID NO: 389 AAV2 variant 2711 WO2018071831 SEQ ID NO: 390 AAV2 variant 2712 WO2018071831 SEQ ID NO: 391 AAV2 variant 2713 WO2018071831 SEQ ID NO: 392 AAV2 variant 2714 WO2018071831 SEQ ID NO: 393 AAV2 variant 2715 WO2018071831 SEQ ID NO: 394 AAV2 variant 2716 WO2018071831 SEQ ID NO: 395 AAV2 variant 2717 WO2018071831 SEQ ID NO: 396 AAV2 variant 2718 WO2018071831 SEQ ID NO: 397 AAV2 variant 2719 WO2018071831 SEQ ID NO: 398 AAV2 variant 2720 WO2018071831 SEQ ID NO: 399 AAV2 variant 2721 WO2018071831 SEQ ID NO: 400 AAV2 variant 2722 WO2018071831 SEQ ID NO: 401 AAV2 variant 2723 WO2018071831 SEQ ID NO: 402 AAV2 variant 2724 WO2018071831 SEQ ID NO: 403 AAV2 variant 2725 WO2018071831 SEQ ID NO: 404 AAV2 variant 2726 WO2018071831 SEQ ID NO: 405 AAV2 variant 2727 WO2018071831 SEQ ID NO: 406 AAV2 variant 2728 WO2018071831 SEQ ID NO: 407 AAV2 variant 2729 WO2018071831 SEQ ID NO: 408 AAV2 variant 2730 WO2018071831 SEQ ID NO: 409 AAV2/3 variant 2731 WO2018071831 SEQ ID NO: 435 AAV2/3 variant 2732 WO2018071831 SEQ ID NO: 436 AAV2/3 variant 2733 WO2018071831 SEQ ID NO: 437 AAV2/3 variant 2734 WO2018071831 SEQ ID NO: 438 AAV2/3 variant 2735 WO2018071831 SEQ ID NO: 439 AAV2/3 variant 2736 WO2018071831 SEQ ID NO: 440 AAV2/3 variant 2737 WO2018071831 SEQ ID NO: 441 AAV2/3 variant 2738 WO2018071831 SEQ ID NO: 442 AAV2/3 variant 2739 WO2018071831 SEQ ID NO: 443 AAV2/3 variant 2740 WO2018071831 SEQ ID NO: 444 AAV2/3 variant 2744 WO2018071831 SEQ ID NO: 445 AAV2/3 variant 2742 WO2018071831 SEQ ID NO: 446 AAV2/3 variant 2743 WO2018071831 SEQ ID NO: 447 AAV2/3 variant 2744 WO2018071831 SEQ ID NO: 448 AAV2/3 variant 2745 WO2018071831 SEQ ID NO: 449 AAV2/3 variant 2746 WO2018071831 SEQ ID NO: 450 AAV2/3 variant 2747 WO2018071831 SEQ ID NO: 451 AAV2/3 variant 2748 WO2018071831 SEQ ID NO: 452 AAV2/3 variant 2749 WO2018071831 SEQ ID NO: 453 AAV2/3 variant 2750 WO2018071831 SEQ ID NO: 454 AAV2/3 variant 2751 WO2018071831 SEQ ID NO: 455 AAV2/3 variant 2752 WO2018071831 SEQ ID NO: 456 AAV2/3 variant 2753 WO2018071831 SEQ ID NO: 457 AAV2/3 variant 2754 WO2018071831 SEQ ID NO: 458 AAV2/3 variant 2755 WO2018071831 SEQ ID NO: 459 AAV2/3 variant 2756 WO2018071831 SEQ ID NO: 460 AAV2/3 variant 2757 WO2018071831 SEQ ID NO: 461 AAV2/3 variant 2758 WO2018071831 SEQ ID NO: 462 AAV2/3 variant 2759 WO2018071831 SEQ ID NO: 463 AAV2/3 variant 2760 WO2018071831 SEQ ID NO: 464 AAV2/3 variant 2761 WO2018071831 SEQ ID NO: 465 AAV2/3 variant 2762 WO2018071831 SEQ ID NO: 466 AAV2/3 variant 2763 WO2018071831 SEQ ID NO: 467 AAV2/3 variant 2764 WO2018071831 SEQ ID NO: 468 AAV2/3 variant 2765 WO2018071831 SEQ ID NO: 469 AAV2/3 variant 2766 WO2018071831 SEQ ID NO: 470 AAV2/3 variant 2767 WO2018071831 SEQ ID NO: 471 AAV2/3 variant 2768 WO2018071831 SEQ ID NO: 472 AAV2/3 variant 2769 WO2018071831 SEQ ID NO: 473 AAV2/3 variant 2770 WO2018071831 SEQ ID NO: 474 AAV2/3 variant 2771 WO2018071831 SEQ ID NO: 475 AAV2/3 variant 2772 WO2018071831 SEQ ID NO: 476 AAV2/3 variant 2773 WO2018071831 SEQ ID NO: 477 AAV2/3 variant 2774 WO2018071831 SEQ ID NO: 478 AAV2/3 variant 2775 WO2018071831 SEQ ID NO: 479 AAV2/3 variant 2776 WO2018071831 SEQ ID NO: 480 AAV2/3 variant 2777 WO2018071831 SEQ ID NO: 481 AAV2/3 variant 2778 WO2018071831 SEQ ID NO: 482 AAV2/3 variant 2779 WO2018071831 SEQ ID NO: 483 AAV2/3 variant 2780 WO2018071831 SEQ ID NO: 484 AAV2/3 variant 2781 WO2018071831 SEQ ID NO: 485 AAV2/3 variant 2782 WO2018071831 SEQ ID NO: 486 AAV2/3 variant 2783 WO2018071831 SEQ ID NO: 487 AAV2/3 variant 2784 WO2018071831 SEQ ID NO: 488 AAV2/3 variant 2785 WO2018071831 SEQ ID NO: 489 AAV2/3 variant 2786 WO2018071831 SEQ ID NO: 490 AAV2/3 variant 2787 WO2018071831 SEQ ID NO: 491 AAV2/3 variant 2788 WO2018071831 SEQ ID NO: 492 AAV2/3 variant 2789 WO2018071831 SEQ ID NO: 493 AAV2/3 variant 2790 WO2018071831 SEQ ID NO: 494 AAV2/3 variant 2791 WO2018071831 SEQ ID NO: 495 AAV2/3 variant 2792 WO2018071831 SEQ ID NO: 496 AAV2/3 variant 2793 WO2018071831 SEQ ID NO: 497 AAV2/3 variant 2794 WO2018071831 SEQ ID NO: 498 AAV2/3 variant 2795 WO2018071831 SEQ ID NO: 499 AAV2/3 variant 2796 WO2018071831 SEQ ID NO: 500 AAV2/3 variant 2797 WO2018071831 SEQ ID NO: 501 AAV2/3 variant 2798 WO2018071831 SEQ ID NO: 502 AAV2/3 variant 2799 WO2018071831 SEQ ID NO: 503 AAV2/3 variant 2800 WO2018071831 SEQ ID NO: 504 AAV2/3 variant 2801 WO2018071831 SEQ ID NO: 505 AAV2/3 variant 2802 WO2018071831 SEQ ID NO: 506 AAV2/3 variant 2803 WO2018071831 SEQ ID NO: 507 AAV2/3 variant 2804 WO2018071831 SEQ ID NO: 508 AAV2/3 variant 2805 WO2018071831 SEQ ID NO: 509 AAV2/3 variant 2806 WO2018071831 SEQ ID NO: 510 AAV2/3 variant 2807 WO2018071831 SEQ ID NO: 511 AAV2/3 variant 2808 WO2018071831 SEQ ID NO: 512 AAV2/3 variant 2809 WO2018071831 SEQ ID NO: 513 AAV2/3 variant 2810 WO2018071831 SEQ ID NO: 514 AAV2/3 variant 2811 WO2018071831 SEQ ID NO: 515 AAV2/3 variant 2812 WO2018071831 SEQ ID NO: 516 AAV2/3 variant 2813 WO2018071831 SEQ ID NO: 517 AAV2/3 variant 2814 WO2018071831 SEQ ID NO: 518 AAV2/3 variant 2815 WO2018071831 SEQ ID NO: 519 AAV2/3 variant 2816 WO2018071831 SEQ ID NO: 520 AAV2/3 variant 2817 WO2018071831 SEQ ID NO: 521 AAV2/3 variant 2818 WO2018071831 SEQ ID NO: 522 AAV2/3 variant 2819 WO2018071831 SEQ ID NO: 523 AAV2/3 variant 2820 WO2018071831 SEQ ID NO: 524 AAV2/3 variant 2821 WO2018071831 SEQ ID NO: 525 AAV2/3 variant 2822 WO2018071831 SEQ ID NO: 526 AAV2/3 variant 2823 WO2018071831 SEQ ID NO: 527 AAV2/3 variant 2824 WO2018071831 SEQ ID NO: 528 AAV2/3 variant 2825 WO2018071831 SEQ ID NO: 529 AAV2/3 variant 2826 WO2018071831 SEQ ID NO: 530 AAV2/3 variant 2827 WO2018071831 SEQ ID NO: 531 AAV2/3 variant 2828 WO2018071831 SEQ ID NO: 532 AAV2/3 variant 2829 WO2018071831 SEQ ID NO: 533 AAV2/3 variant 2830 WO2018071831 SEQ ID NO: 534 AAV2/3 variant 2831 WO2018071831 SEQ ID NO: 535 AAV2/3 variant 2832 WO2018071831 SEQ ID NO: 536 AAV2/3 variant 2833 WO2018071831 SEQ ID NO: 537 AAV2/3 variant 2834 WO2018071831 SEQ ID NO: 538 AAV2/3 variant 2835 WO2018071831 SEQ ID NO: 539 AAV2/3 variant 2836 WO2018071831 SEQ ID NO: 540 AAV2/3 variant 2837 WO2018071831 SEQ ID NO: 541 AAV2/3 variant 2838 WO2018071831 SEQ ID NO: 542 AAV2/3 variant 2839 WO2018071831 SEQ ID NO: 543 AAV2/3 variant 2840 WO2018071831 SEQ ID NO: 544 AAV2/3 variant 2841 WO2018071831 SEQ ID NO: 545 AAV2/3 variant 2842 WO2018071831 SEQ ID NO: 546 AAV2/3 variant 2843 WO2018071831 SEQ ID NO: 547 AAV2/3 variant 2844 WO2018071831 SEQ ID NO: 548 AAV2/3 variant 2845 WO2018071831 SEQ ID NO: 549 AAV2/3 variant 2846 WO2018071831 SEQ ID NO: 550 AAV2/3 variant 2847 WO2018071831 SEQ ID NO: 551 AAV2/3 variant 2848 WO2018071831 SEQ ID NO: 552 AAV2/3 variant 2849 WO2018071831 SEQ ID NO: 553 AAV2/3 variant 2850 WO2018071831 SEQ ID NO: 554 AAV2/3 variant 2851 WO2018071831 SEQ ID NO: 555 AAV2/3 variant 2852 WO2018071831 SEQ ID NO: 556 AAV2/3 variant 2853 WO2018071831 SEQ ID NO: 557 AAV2/3 variant 2854 WO2018071831 SEQ ID NO: 558 AAV2/3 variant 2855 WO2018071831 SEQ ID NO: 559 AAV2/3 variant 2856 WO2018071831 SEQ ID NO: 560 AAV2/3 variant 2857 WO2018071831 SEQ ID NO: 561 AAV2/3 variant 2858 WO2018071831 SEQ ID NO: 562 AAV2/3 variant 2859 WO2018071831 SEQ ID NO: 563 AAV2/3 variant 2860 WO2018071831 SEQ ID NO: 564 AAV2/3 variant 2861 WO2018071831 SEQ ID NO: 565 AAV2/3 variant 2862 WO2018071831 SEQ ID NO: 566 AAV2/3 variant 2863 WO2018071831 SEQ ID NO: 567 AAV2/3 variant 2864 WO2018071831 SEQ ID NO: 568 AAV2/3 variant 2865 WO2018071831 SEQ ID NO: 569 AAV2/3 variant 2866 WO2018071831 SEQ ID NO: 570 AAV2/3 variant 2867 WO2018071831 SEQ ID NO: 571 AAV2/3 variant 2868 WO2018071831 SEQ ID NO: 572 AAV2/3 variant 2869 WO2018071831 SEQ ID NO: 573 AAV2/3 variant 2870 WO2018071831 SEQ ID NO: 574 AAV2/3 variant 2871 WO2018071831 SEQ ID NO: 575 AAV2/3 variant 2872 WO2018071831 SEQ ID NO: 576 AAV2/3 variant 2873 WO2018071831 SEQ ID NO: 577 AAV2/3 variant 2874 WO2018071831 SEQ ID NO: 578 AAV2/3 variant 2875 WO2018071831 SEQ ID NO: 579 AAV2/3 variant 2876 WO2018071831 SEQ ID NO: 580 AAV2/3 variant 2877 WO2018071831 SEQ ID NO: 581 AAV2/3 variant 2878 WO2018071831 SEQ ID NO: 582 AAV2/3 variant 2879 WO2018071831 SEQ ID NO: 583 AAV2/3 variant 2880 WO2018071831 SEQ ID NO: 584 AAV2/3 variant 2881 WO2018071831 SEQ ID NO: 585 AAV2/3 variant 2882 WO2018071831 SEQ ID NO: 586 AAV2/3 variant 2883 WO2018071831 SEQ ID NO: 587 AAV2/3 variant 2884 WO2018071831 SEQ ID NO: 588 AAV2/3 variant 2885 WO2018071831 SEQ ID NO: 589 AAV2/3 variant 2886 WO2018071831 SEQ ID NO: 590 AAV2/3 variant 2887 WO2018071831 SEQ ID NO: 591 AAV2/3 variant 2888 WO2018071831 SEQ ID NO: 592 AAV2/3 variant 2889 WO2018071831 SEQ ID NO: 593 AAV2/3 variant 2890 WO2018071831 SEQ ID NO: 594 AAV2/3 variant 2891 WO2018071831 SEQ ID NO: 595 AAV2/3 variant 2892 WO2018071831 SEQ ID NO: 596 AAV2/3 variant 2893 WO2018071831 SEQ ID NO: 597 AAV2/3 variant 2894 WO2018071831 SEQ ID NO: 598 AAV2/3 variant 2895 WO2018071831 SEQ ID NO: 599 AAV2/3 variant 2896 WO2018071831 SEQ ID NO: 600 AAV2/3 variant 2897 WO2018071831 SEQ ID NO: 601 AAV2/3 variant 2898 WO2018071831 SEQ ID NO: 602 AAV2/3 variant 2899 WO2018071831 SEQ ID NO: 603 AAV2/3 variant 2900 WO2018071831 SEQ ID NO: 604 AAV2/3 variant 2901 WO2018071831 SEQ ID NO: 605 AAV2/3 variant 2902 WO2018071831 SEQ ID NO: 606 AAV2/3 variant 2903 WO2018071831 SEQ ID NO: 607 AAV2/3 variant 2904 WO2018071831 SEQ ID NO: 608 AAV2/3 variant 2905 WO2018071831 SEQ ID NO: 609 AAV2/3 variant 2906 WO2018071831 SEQ ID NO: 610 AAV2/3 variant 2907 WO2018071831 SEQ ID NO: 611 AAV2/3 variant 2908 WO2018071831 SEQ ID NO: 612 AAV2/3 variant 2909 WO2018071831 SEQ ID NO: 613 AAV2/3 variant 2910 WO2018071831 SEQ ID NO: 614 AAV2/3 variant 2911 WO2018071831 SEQ ID NO: 615 AAV2/3 variant 2912 WO2018071831 SEQ ID NO: 616 AAV2/3 variant 2913 WO2018071831 SEQ ID NO: 617 AAV2/3 variant 2914 WO2018071831 SEQ ID NO: 618 AAV2/3 variant 2915 WO2018071831 SEQ ID NO: 619 AAV2/3 variant 2916 WO2018071831 SEQ ID NO: 620 AAV2/3 variant 2917 WO2018071831 SEQ ID NO: 621 AAV2/3 variant 2918 WO2018071831 SEQ ID NO: 622 AAV2/3 variant 2919 WO2018071831 SEQ ID NO: 623 AAV2/3 variant 2920 WO2018071831 SEQ ID NO: 624 AAV2/3 variant 2921 WO2018071831 SEQ ID NO: 625 AAV2/3 variant 2922 WO2018071831 SEQ ID NO: 626 AAV2/3 variant 2923 WO2018071831 SEQ ID NO: 627 AAV2/3 variant 2924 WO2018071831 SEQ ID NO: 628 AAV8 Variant 2925 WO2018071831 SEQ ID NO: 629 AAV8 Variant 2926 WO2018071831 SEQ ID NO: 630 AAV8 Variant 2927 WO2018071831 SEQ ID NO: 631 AAV8 Variant 2928 WO2018071831 SEQ ID NO: 632 AAV8 Variant 2929 WO2018071831 SEQ ID NO: 633 AAV8 Variant 2930 WO2018071831 SEQ ID NO: 634 AAV8 Variant 2931 WO2018071831 SEQ ID NO: 635 AAV8 Variant 2932 WO2018071831 SEQ ID NO: 636 AAV8 Variant 2933 WO2018071831 SEQ ID NO: 637 AAV8 Variant 2934 WO2018071831 SEQ ID NO: 638 AAV8 Variant 2935 WO2018071831 SEQ ID NO: 639 AAV8 Variant 2936 WO2018071831 SEQ ID NO: 640 AAV8 Variant 2937 WO2018071831 SEQ ID NO: 641 AAV8 Variant 2938 WO2018071831 SEQ ID NO: 642 AAV8 Variant 2939 WO2018071831 SEQ ID NO: 643 AAV8 Variant 2940 WO2018071831 SEQ ID NO: 644 AAV8 Variant 2941 WO2018071831 SEQ ID NO: 645 AAV8 Variant 2942 WO2018071831 SEQ ID NO: 646 AAV8 Variant 2943 WO2018071831 SEQ ID NO: 647 AAV8 Variant 2944 WO2018071831 SEQ ID NO: 648 AAV8 Variant 2945 WO2018071831 SEQ ID NO: 649 AAV8 Variant 2946 WO2018071831 SEQ ID NO: 650 AAV8 Variant 2947 WO2018071831 SEQ ID NO: 651 AAV8 Variant 2948 WO2018071831 SEQ ID NO: 652 AAV8 Variant 2949 WO2018071831 SEQ ID NO: 653 AAV8 Variant 2950 WO2018071831 SEQ ID NO: 654 AAV8 Variant 2951 WO2018071831 SEQ ID NO: 655 AAV8 Variant 2952 WO2018071831 SEQ ID NO: 656 AAV8 Variant 2953 WO2018071831 SEQ ID NO: 657 AAV8 Variant 2954 WO2018071831 SEQ ID NO: 658 AAV8 Variant 2955 WO2018071831 SEQ ID NO: 659 AAV8 Variant 2956 WO2018071831 SEQ ID NO: 660 AAV8 Variant 2957 WO2018071831 SEQ ID NO: 661 AAV8 Variant 2958 WO2018071831 SEQ ID NO: 662 AAV8 Variant 2959 WO2018071831 SEQ ID NO: 663 AAV8 Variant 2960 WO2018071831 SEQ ID NO: 664 AAV8 Variant 2961 WO2018071831 SEQ ID NO: 665 AAV8 Variant 2962 WO2018071831 SEQ ID NO: 666 AAV8 Variant 2963 WO2018071831 SEQ ID NO: 667 AAV8 Variant 2964 WO2018071831 SEQ ID NO: 668 AAV8 Variant 2965 WO2018071831 SEQ ID NO: 669 AAV8 Variant 2966 WO2018071831 SEQ ID NO: 670 AAV8 Variant 2967 WO2018071831 SEQ ID NO: 671 AAV8 Variant 2968 WO2018071831 SEQ ID NO: 672 AAV8 Variant 2969 WO2018071831 SEQ ID NO: 673 AAV8 Variant 2970 WO2018071831 SEQ ID NO: 674 AAV8 Variant 2971 WO2018071831 SEQ ID NO: 675 AAV8 Variant 2972 WO2018071831 SEQ ID NO: 676 AAV8 Variant 2973 WO2018071831 SEQ ID NO: 677 AAV8 Variant 2974 WO2018071831 SEQ ID NO: 678 AAV8 Variant 2975 WO2018071831 SEQ ID NO: 679 AAV8 Variant 2976 WO2018071831 SEQ ID NO: 680 AAV8 Variant 2977 WO2018071831 SEQ ID NO: 681 AAV8 Variant 2978 WO2018071831 SEQ ID NO: 682 AAV8 Variant 2979 WO2018071831 SEQ ID NO: 683 AAV8 Variant 2980 WO2018071831 SEQ ID NO: 684 AAV8 Variant 2981 WO2018071831 SEQ ID NO: 685 AAV8 Variant 2982 WO2018071831 SEQ ID NO: 686 AAV8 Variant 2983 WO2018071831 SEQ ID NO: 687 AAV8 Variant 2984 WO2018071831 SEQ ID NO: 688 AAV8 Variant 2985 WO2018071831 SEQ ID NO: 689 AAV8 Variant 2986 WO2018071831 SEQ ID NO: 690 AAV8 Variant 2987 WO2018071831 SEQ ID NO: 691 AAV8 Variant 2988 WO2018071831 SEQ ID NO: 692 AAV8 Variant 2989 WO2018071831 SEQ ID NO: 693 AAV8 Variant 2990 WO2018071831 SEQ ID NO: 694 AAV8 Variant 2991 WO2018071831 SEQ ID NO: 695 AAV8 Variant 2992 WO2018071831 SEQ ID NO: 696 AAV8 Variant 2993 WO2018071831 SEQ ID NO: 697 AAV8 Variant 2994 WO2018071831 SEQ ID NO: 698 AAV8 Variant 2995 WO2018071831 SEQ ID NO: 699 AAV8 Variant 2996 WO2018071831 SEQ ID NO: 700 AAV8 Variant 2997 WO2018071831 SEQ ID NO: 701 AAV8 Variant 2998 WO2018071831 SEQ ID NO: 702 AAV8 Variant 2999 WO2018071831 SEQ ID NO: 703 AAV8 Variant 3000 WO2018071831 SEQ ID NO: 704 AAV8 Variant 3001 WO2018071831 SEQ ID NO: 705 AAV8 Variant 3002 WO2018071831 SEQ ID NO: 706 AAV8 Variant 3003 WO2018071831 SEQ ID NO: 707 AAV8 Variant 3004 WO2018071831 SEQ ID NO: 708 AAV8 Variant 3005 WO2018071831 SEQ ID NO: 709 AAV8 Variant 3006 WO2018071831 SEQ ID NO: 710 AAV8 Variant 3007 WO2018071831 SEQ ID NO: 711 AAV8 Variant 3008 WO2018071831 SEQ ID NO: 712 AAV8 Variant 3009 WO2018071831 SEQ ID NO: 713 AAV8 Variant 3010 WO2018071831 SEQ ID NO: 714 AAV8 Variant 3011 WO2018071831 SEQ ID NO: 715 AAV8 Variant 3012 WO2018071831 SEQ ID NO: 716 AAV8 Variant 3013 WO2018071831 SEQ ID NO: 717 AAV8 Variant 3014 WO2018071831 SEQ ID NO: 718 AAV8 Variant 3015 WO2018071831 SEQ ID NO: 719 AAV8 Variant 3016 WO2018071831 SEQ ID NO: 720 AAV8 Variant 3017 WO2018071831 SEQ ID NO: 721 AAV8 Variant 3018 WO2018071831 SEQ ID NO: 722 AAV8 Variant 3019 WO2018071831 SEQ ID NO: 723 AAV8 Variant 3020 WO2018071831 SEQ ID NO: 724 AAV8 Variant 3021 WO2018071831 SEQ ID NO: 725 AAV8 Variant 3022 WO2018071831 SEQ ID NO: 726 AAV8 Variant 3023 WO2018071831 SEQ ID NO: 727 AAV8 Variant 3024 WO2018071831 SEQ ID NO: 728 AAV8 Variant 3025 WO2018071831 SEQ ID NO: 729 AAV8 Variant 3026 WO2018071831 SEQ ID NO: 730 AAV8 Variant 3027 WO2018071831 SEQ ID NO: 731 AAV8 Variant 3028 WO2018071831 SEQ ID NO: 732 AAV8 Variant 3029 WO2018071831 SEQ ID NO: 733 AAV8 Variant 3030 WO2018071831 SEQ ID NO: 734 AAV8 Variant 3031 WO2018071831 SEQ ID NO: 735 AAV8 Variant 3032 WO2018071831 SEQ ID NO: 736 AAV8 Variant 3033 WO2018071831 SEQ ID NO: 737 AAV8 Variant 3034 WO2018071831 SEQ ID NO: 738 AAV8 Variant 3035 WO2018071831 SEQ ID NO: 739 AAV8 Variant 3036 WO2018071831 SEQ ID NO: 740 AAV8 Variant 3037 WO2018071831 SEQ ID NO: 741 AAV8 Variant 3038 WO2018071831 SEQ ID NO: 742 AAV8 Variant 3039 WO2018071831 SEQ ID NO: 743 AAV8 Variant 3040 WO2018071831 SEQ ID NO: 744 AAV8 Variant 3041 WO2018071831 SEQ ID NO: 745 AAV8 Variant 3042 WO2018071831 SEQ ID NO: 746 AAV8 Variant 3043 WO2018071831 SEQ ID NO: 747 AAV8 Variant 3044 WO2018071831 SEQ ID NO: 748 AAV8 Variant 3045 WO2018071831 SEQ ID NO: 749 AAV8 Variant 3046 WO2018071831 SEQ ID NO: 750 AAV8 Variant 3047 WO2018071831 SEQ ID NO: 751 AAV8 Variant 3048 WO2018071831 SEQ ID NO: 752 AAV8 Variant 3049 WO2018071831 SEQ ID NO: 753 AAV8 Variant 3050 WO2018071831 SEQ ID NO: 754 AAV8 Variant 3051 WO2018071831 SEQ ID NO: 755 AAV8 Variant 3052 WO2018071831 SEQ ID NO: 756 AAV8 Variant 3053 WO2018071831 SEQ ID NO: 757 AAV8 Variant 3054 WO2018071831 SEQ ID NO: 758 AAV8 Variant 3055 WO2018071831 SEQ ID NO: 759 AAV8 Variant 3056 WO2018071831 SEQ ID NO: 760 AAV8 Variant 3057 WO2018071831 SEQ ID NO: 761 AAV8 Variant 3058 WO2018071831 SEQ ID NO: 762 AAV8 Variant 3059 WO2018071831 SEQ ID NO: 763 AAV8 Variant 3060 WO2018071831 SEQ ID NO: 764 AAV8 Variant 3061 WO2018071831 SEQ ID NO: 765 AAV8 Variant 3062 WO2018071831 SEQ ID NO: 766 AAV8 Variant 3063 WO2018071831 SEQ ID NO: 767 AAV8 Variant 3064 WO2018071831 SEQ ID NO: 768 AAV8 Variant 3065 WO2018071831 SEQ ID NO: 769 AAV8 Variant 3066 WO2018071831 SEQ ID NO: 770 AAV8 Variant 3067 WO2018071831 SEQ ID NO: 771 AAV8 Variant 3068 WO2018071831 SEQ ID NO: 772 AAV8 Variant 3069 WO2018071831 SEQ ID NO: 773 AAV8 Variant 3070 WO2018071831 SEQ ID NO: 774 AAV8 Variant 3071 WO2018071831 SEQ ID NO: 775 AAV8 Variant 3072 WO2018071831 SEQ ID NO: 776 AAV8 Variant 3073 WO2018071831 SEQ ID NO: 777 AAV8 Variant 3074 WO2018071831 SEQ ID NO: 778 AAV8 Variant 3075 WO2018071831 SEQ ID NO: 779 AAV8 Variant 3076 WO2018071831 SEQ ID NO: 780 AAV8 Variant 3077 WO2018071831 SEQ ID NO: 781 AAV8 Variant 3078 WO2018071831 SEQ ID NO: 782 AAV8 Variant 3079 WO2018071831 SEQ ID NO: 783 AAV8 Variant 3080 WO2018071831 SEQ ID NO: 784 AAV8 Variant 3081 WO2018071831 SEQ ID NO: 785 AAV8 Variant 3082 WO2018071831 SEQ ID NO: 786 AAV8 Variant 3083 WO2018071831 SEQ ID NO: 787 AAV8 Variant 3084 WO2018071831 SEQ ID NO: 788 AAV8 Variant 3085 WO2018071831 SEQ ID NO: 789 AAV8 Variant 3086 WO2018071831 SEQ ID NO: 790 AAV8 Variant 3087 WO2018071831 SEQ ID NO: 791 AAV8 Variant 3088 WO2018071831 SEQ ID NO: 792 AAV8 Variant 3089 WO2018071831 SEQ ID NO: 793 AAV8 Variant 3090 WO2018071831 SEQ ID NO: 794 AAV8 Variant 3091 WO2018071831 SEQ ID NO: 795 AAV8 Variant 3092 WO2018071831 SEQ ID NO: 796 AAV8 Variant 3093 WO2018071831 SEQ ID NO: 797 AAV8 Variant 3094 WO2018071831 SEQ ID NO: 798 AAV8 Variant 3095 WO2018071831 SEQ ID NO: 799 AAV8 Variant 3096 WO2018071831 SEQ ID NO: 800 AAV8 Variant 3097 WO2018071831 SEQ ID NO: 801 AAV8 Variant 3098 WO2018071831 SEQ ID NO: 802 AAV8 Variant 3099 WO2018071831 SEQ ID NO: 803 AAV8 Variant 3100 WO2018071831 SEQ ID NO: 804 AAV8 Variant 3101 WO2018071831 SEQ ID NO: 805 AAV8 Variant 3102 WO2018071831 SEQ ID NO: 806 AAV8 Variant 3103 WO2018071831 SEQ ID NO: 807 AAV8 Variant 3104 WO2018071831 SEQ ID NO: 808 AAV8 Variant 3105 WO2018071831 SEQ ID NO: 809 AAV8 Variant 3106 WO2018071831 SEQ ID NO: 810 AAV8 Variant 3107 WO2018071831 SEQ ID NO: 811 AAV8 Variant 3108 WO2018071831 SEQ ID NO: 812 AAV8 Variant 3109 WO2018071831 SEQ ID NO: 813 AAV8 Variant 3110 WO2018071831 SEQ ID NO: 814 AAV8 Variant 3111 WO2018071831 SEQ ID NO: 815 AAV8 Variant 3112 WO2018071831 SEQ ID NO: 816 AAV8 Variant 3113 WO2018071831 SEQ ID NO: 817 AAV8 Variant 3114 WO2018071831 SEQ ID NO: 818 AAV8 Variant 3115 WO2018071831 SEQ ID NO: 819 AAV8 Variant 3116 WO2018071831 SEQ ID NO: 820 AAV8 Variant 3117 WO2018071831 SEQ ID NO: 821 AAV8 Variant 3118 WO2018071831 SEQ ID NO: 822 AAV8 Variant 3119 WO2018071831 SEQ ID NO: 823 AAV8 Variant 3120 WO2018071831 SEQ ID NO: 824 AAV8 Variant 3121 WO2018071831 SEQ ID NO: 825 AAV8 Variant 3122 WO2018071831 SEQ ID NO: 826 AAV8 Variant 3123 WO2018071831 SEQ ID NO: 827 AAV8 Variant 3124 WO2018071831 SEQ ID NO: 828 AAV8 Variant 3125 WO2018071831 SEQ ID NO: 829 AAV8 Variant 3126 WO2018071831 SEQ ID NO: 830 AAV8 Variant 3127 WO2018071831 SEQ ID NO: 831 AAV8 Variant 3128 WO2018071831 SEQ ID NO: 832 AAV8 Variant 3129 WO2018071831 SEQ ID NO: 833 AAV8 Variant 3130 WO2018071831 SEQ ID NO: 834 AAV8 Variant 3131 WO2018071831 SEQ ID NO: 835 AAV8 Variant 3132 WO2018071831 SEQ ID NO: 836 AAV2 variant 3133 WO2018071831 SEQ ID NO: 837 AAV2 variant 3134 WO2018071831 SEQ ID NO: 838 AAV2 variant 3135 WO2018071831 SEQ ID NO: 839 AAV2 variant 3136 WO2018071831 SEQ ID NO: 840 AAV2 variant 3137 WO2018071831 SEQ ID NO: 841 AAV2 variant 3138 WO2018071831 SEQ ID NO: 842 AAV2 variant 3139 WO2018071831 SEQ ID NO: 843 AAV2 variant 3140 WO2018071831 SEQ ID NO: 844 AAV2 variant 3141 WO2018071831 SEQ ID NO: 845 AAV2 variant 3142 WO2018071831 SEQ ID NO: 846 AAV2 variant 3143 WO2018071831 SEQ ID NO: 847 AAV2 variant 3144 WO2018071831 SEQ ID NO: 848 AAV2 variant 3145 WO2018071831 SEQ ID NO: 849 AAV2 variant 3146 WO2018071831 SEQ ID NO: 850 AAV2 variant 3147 WO2018071831 SEQ ID NO: 851 AAV2 variant 3148 WO2018071831 SEQ ID NO: 852 AAV8 B1 3149 WO2018071831 SEQ ID NO: 853 AAV8 B2 3150 WO2018071831 SEQ ID NO: 854 AAV8 B3 3151 WO2018071831 SEQ ID NO: 855 AAV8 B4 3152 WO2018071831 SEQ ID NO: 856 AAV8 B12 3153 WO2018071831 SEQ ID NO: 857 AAV8 B18 3154 WO2018071831 SEQ ID NO: 858 AAV8 B24 3155 WO2018071831 SEQ ID NO: 859 AAV8 B41 3156 WO2018071831 SEQ ID NO: 860 AAV8 B44 3157 WO2018071831 SEQ ID NO: 861 AAV8 B45 3158 WO2018071831 SEQ ID NO: 862 AAV8 B46 3159 WO2018071831 SEQ ID NO: 863 AAV8 B60 3160 WO2018071831 SEQ ID NO: 864 AAV8 B61 3161 WO2018071831 SEQ ID NO: 865 AAV8 B62 3162 WO2018071831 SEQ ID NO: 866 AAV8 B63 3163 WO2018071831 SEQ ID NO: 867 AAV8 B64 3164 WO2018071831 SEQ ID NO: 868 AAV variant 3165 WO2018071831 SEQ ID NO: 876 AAV variant 3166 WO2018071831 SEQ ID NO: 877 AAV variant 3167 WO2018071831 SEQ ID NO: 878 AAV variant 3168 WO2018071831 SEQ ID NO: 879 AAV variant 3169 WO2018071831 SEQ ID NO: 880 AAV variant 3170 WO2018071831 SEQ ID NO: 881 AAV variant 3171 WO2018071831 SEQ ID NO: 882 AAV variant 3172 WO2018071831 SEQ ID NO: 883 AAV variant 3173 WO2018071831 SEQ ID NO: 884 AAV variant 3174 WO2018071831 SEQ ID NO: 885 AAV variant 3175 WO2018071831 SEQ ID NO: 886 AAV variant 3176 WO2018071831 SEQ ID NO: 887 AAV variant 3177 WO2018071831 SEQ ID NO: 888 AAV variant 3178 WO2018071831 SEQ ID NO: 889 AAV variant 3179 WO2018071831 SEQ ID NO: 890 AAV variant 3180 WO2018071831 SEQ ID NO: 891 AAV variant 3181 WO2018071831 SEQ ID NO: 892 AAV variant 3182 WO2018071831 SEQ ID NO: 893 AAV variant 3183 WO2018071831 SEQ ID NO: 894 AAV variant 3184 WO2018071831 SEQ ID NO: 895 AAV variant 3185 WO2018071831 SEQ ID NO: 896 AAV variant 3186 WO2018071831 SEQ ID NO: 897 AAV variant 3187 WO2018071831 SEQ ID NO: 898 AAV variant 3188 WO2018071831 SEQ ID NO: 899 AAV variant 3189 WO2018071831 SEQ ID NO: 900 AAV variant 3190 WO2018071831 SEQ ID NO: 901 AAV variant 3191 WO2018071831 SEQ ID NO: 902 AAV variant 3192 WO2018071831 SEQ ID NO: 903 AAV variant 3193 WO2018071831 SEQ ID NO: 904 AAV variant 3194 WO2018071831 SEQ ID NO: 905 AAV variant 3195 WO2018071831 SEQ ID NO: 906 AAV variant 3196 WO2018071831 SEQ ID NO: 907 AAV variant 3197 WO2018071831 SEQ ID NO: 908 AAV variant 3198 WO2018071831 SEQ ID NO: 909 AAV variant 3199 WO2018071831 SEQ ID NO: 910 AAV variant 3200 WO2018071831 SEQ ID NO: 911 AAV variant 3201 WO2018071831 SEQ ID NO: 912 AAV variant 3202 WO2018071831 SEQ ID NO: 913 AAV variant 3203 WO2018071831 SEQ ID NO: 914 AAV variant 3204 WO2018071831 SEQ ID NO: 915 AAV variant 3205 WO2018071831 SEQ ID NO: 916 AAV variant 3206 WO2018071831 SEQ ID NO: 917 AAV variant 3207 WO2018071831 SEQ ID NO: 918 AAV variant 3208 WO2018071831 SEQ ID NO: 919 AAV variant 3209 WO2018071831 SEQ ID NO: 920 AAV variant 3210 WO2018071831 SEQ ID NO: 921 AAV variant 3211 WO2018071831 SEQ ID NO: 922 AAV variant 3212 WO2018071831 SEQ ID NO: 923 AAV variant 3213 WO2018071831 SEQ ID NO: 924 AAV variant 3214 WO2018071831 SEQ ID NO: 925 AAV variant 3215 WO2018071831 SEQ ID NO: 926 AAV variant 3216 WO2018071831 SEQ ID NO: 927 AAV variant 3217 WO2018071831 SEQ ID NO: 928 AAV variant 3218 WO2018071831 SEQ ID NO: 929 AAV variant 3219 WO2018071831 SEQ ID NO: 930 AAV variant 3220 WO2018071831 SEQ ID NO: 931 AAV variant 3221 WO2018071831 SEQ ID NO: 932 AAV variant 3222 WO2018071831 SEQ ID NO: 933 AAV variant 3223 WO2018071831 SEQ ID NO: 934 AAV variant 3224 WO2018071831 SEQ ID NO: 935 AAV variant 3225 WO2018071831 SEQ ID NO: 936 AAV variant 3226 WO2018071831 SEQ ID NO: 937 AAV variant 3227 WO2018071831 SEQ ID NO: 938 AAV variant 3228 WO2018071831 SEQ ID NO: 939 AAV variant 3229 WO2018071831 SEQ ID NO: 940 AAV variant 3230 WO2018071831 SEQ ID NO: 941 AAV variant 3231 WO2018071831 SEQ ID NO: 942 AAV variant 3232 WO2018071831 SEQ ID NO: 943 AAV variant 3233 WO2018071831 SEQ ID NO: 944 AAV variant 3234 WO2018071831 SEQ ID NO: 945 AAV variant 3235 WO2018071831 SEQ ID NO: 946 AAV variant 3236 WO2018071831 SEQ ID NO: 947 AAV variant 3237 WO2018071831 SEQ ID NO: 948 AAV variant 3238 WO2018071831 SEQ ID NO: 949 AAV variant 3239 WO2018071831 SEQ ID NO: 950 AAV variant 3240 WO2018071831 SEQ ID NO: 951 AAV variant 3241 WO2018071831 SEQ ID NO: 952 AAV variant 3242 WO2018071831 SEQ ID NO: 953 AAV variant 3243 WO2018071831 SEQ ID NO: 954 AAV variant 3244 WO2018071831 SEQ ID NO: 955 AAV variant 3245 WO2018071831 SEQ ID NO: 956 AAV variant 3246 WO2018071831 SEQ ID NO: 957 AAV variant 3247 WO2018071831 SEQ ID NO: 958 AAV variant 3248 WO2018071831 SEQ ID NO: 959 AAV variant 3249 WO2018071831 SEQ ID NO: 960 AAV variant 3250 WO2018071831 SEQ ID NO: 961 AAV variant 3251 WO2018071831 SEQ ID NO: 962 AAV variant 3252 WO2018071831 SEQ ID NO: 963 AAV variant 3253 WO2018071831 SEQ ID NO: 964 AAV variant 3254 WO2018071831 SEQ ID NO: 965 AAV variant 3255 WO2018071831 SEQ ID NO: 966 AAV variant 3256 WO2018071831 SEQ ID NO: 967 AAV variant 3257 WO2018071831 SEQ ID NO: 968 AAV variant 3258 WO2018071831 SEQ ID NO: 969 AAV variant 3259 WO2018071831 SEQ ID NO: 970 AAV variant 3260 WO2018071831 SEQ ID NO: 971 AAV variant 3261 WO2018071831 SEQ ID NO: 972 AAV variant 3262 WO2018071831 SEQ ID NO: 973 AAV variant 3263 WO2018071831 SEQ ID NO: 974 AAV variant 3264 WO2018071831 SEQ ID NO: 975 AAV variant 3265 WO2018071831 SEQ ID NO: 976 AAV variant 3266 WO2018071831 SEQ ID NO: 977 AAV variant 3267 WO2018071831 SEQ ID NO: 978 AAV variant 3268 WO2018071831 SEQ ID NO: 979 AAV variant 3269 WO2018071831 SEQ ID NO: 980 AAV variant 3270 WO2018071831 SEQ ID NO: 981 AAV variant 3271 WO2018071831 SEQ ID NO: 982 AAV variant 3272 WO2018071831 SEQ ID NO: 983 AAV variant 3273 WO2018071831 SEQ ID NO: 984 AAV variant 3274 WO2018071831 SEQ ID NO: 985 AAV variant 3275 WO2018071831 SEQ ID NO: 986 AAV variant 3276 WO2018071831 SEQ ID NO: 987 AAV variant 3277 WO2018071831 SEQ ID NO: 988 AAV variant 3278 WO2018071831 SEQ ID NO: 989 AAV variant 3279 WO2018071831 SEQ ID NO: 990 AAV variant 3280 WO2018071831 SEQ ID NO: 991 AAV variant 3281 WO2018071831 SEQ ID NO: 992 AAV variant 3282 WO2018071831 SEQ ID NO: 993 AAV variant 3283 WO2018071831 SEQ ID NO: 994 AAV variant 3284 WO2018071831 SEQ ID NO: 995 AAV variant 3285 WO2018071831 SEQ ID NO: 996 AAV variant 3286 WO2018071831 SEQ ID NO: 997 AAV variant 3287 WO2018071831 SEQ ID NO: 998 AAV variant 3288 WO2018071831 SEQ ID NO: 999 AAV variant 3289 WO2018071831 SEQ ID NO: 1000 AAV variant 3290 WO2018071831 SEQ ID NO: 1001 AAV variant 3291 WO2018071831 SEQ ID NO: 1002 AAV variant 3292 WO2018071831 SEQ ID NO: 1003 AAV variant 3293 WO2018071831 SEQ ID NO: 1004 AAV variant 3294 WO2018071831 SEQ ID NO: 1005 AAV variant 3295 WO2018071831 SEQ ID NO: 1006 AAV variant 3296 WO2018071831 SEQ ID NO: 1007 AAV variant 3297 WO2018071831 SEQ ID NO: 1008 AAV variant 3298 WO2018071831 SEQ ID NO: 1009 AAV variant 3299 WO2018071831 SEQ ID NO: 1010 AAV variant 3300 WO2018071831 SEQ ID NO: 1011 AAV variant 3301 WO2018071831 SEQ ID NO: 1012 AAV variant 3302 WO2018071831 SEQ ID NO: 1013 AAV variant 3303 WO2018071831 SEQ ID NO: 1014 AAV variant 3304 WO2018071831 SEQ ID NO: 1015 AAV variant 3305 WO2018071831 SEQ ID NO: 1016 AAV variant 3306 WO2018071831 SEQ ID NO: 1017 AAV variant 3307 WO2018071831 SEQ ID NO: 1018 AAV variant 3308 WO2018071831 SEQ ID NO: 1019 AAV variant 3309 WO2018071831 SEQ ID NO: 1020 AAV variant 3310 WO2018071831 SEQ ID NO: 1021 AAV variant 3311 WO2018071831 SEQ ID NO: 1022 AAV variant 3312 WO2018071831 SEQ ID NO: 1023 AAV variant 3313 WO2018071831 SEQ ID NO: 1024 AAV variant 3314 WO2018071831 SEQ ID NO: 1025 AAV variant 3315 WO2018071831 SEQ ID NO: 1026 AAV variant 3316 WO2018071831 SEQ ID NO: 1027 AAV variant 3317 WO2018071831 SEQ ID NO: 1028 AAV variant 3318 WO2018071831 SEQ ID NO: 1029 AAV variant 3319 WO2018071831 SEQ ID NO: 1030 AAV variant 3320 WO2018071831 SEQ ID NO: 1031 AAV variant 3321 WO2018071831 SEQ ID NO: 1032 AAV variant 3322 WO2018071831 SEQ ID NO: 1033 AAV variant 3323 WO2018071831 SEQ ID NO: 1034 AAV variant 3324 WO2018071831 SEQ ID NO: 1035 AAV variant 3325 WO2018071831 SEQ ID NO: 1036 AAV variant 3326 WO2018071831 SEQ ID NO: 1037 AAV variant 3327 WO2018071831 SEQ ID NO: 1038 AAV variant 3328 WO2018071831 SEQ ID NO: 1039 AAV variant 3329 WO2018071831 SEQ ID NO: 1040 AAV variant 3330 WO2018071831 SEQ ID NO: 1041 AAV variant 3331 WO2018071831 SEQ ID NO: 1042 AAV variant 3332 WO2018071831 SEQ ID NO: 1043 AAV variant 3333 WO2018071831 SEQ ID NO: 1044 AAV variant 3334 WO2018071831 SEQ ID NO: 1045 AAV variant 3335 WO2018071831 SEQ ID NO: 1046 AAV variant 3336 WO2018071831 SEQ ID NO: 1047 AAV variant 3337 WO2018071831 SEQ ID NO: 1048 AAV variant 3338 WO2018071831 SEQ ID NO: 1049 AAV variant 3339 WO2018071831 SEQ ID NO: 1050 AAV variant 3340 WO2018071831 SEQ ID NO: 1051 AAV variant 3341 WO2018071831 SEQ ID NO: 1052 AAV variant 3342 WO2018071831 SEQ ID NO: 1053 AAV variant 3343 WO2018071831 SEQ ID NO: 1054 AAV variant 3344 WO2018071831 SEQ ID NO: 1055 AAV variant 3345 WO2018071831 SEQ ID NO: 1056 AAV variant 3346 WO2018071831 SEQ ID NO: 1057 AAV variant 3347 WO2018071831 SEQ ID NO: 1058 AAV variant 3348 WO2018071831 SEQ ID NO: 1059 AAV variant 3349 WO2018071831 SEQ ID NO: 1060 AAV variant 3350 WO2018071831 SEQ ID NO: 1061 AAV variant 3351 WO2018071831 SEQ ID NO: 1062 AAV variant 3352 WO2018071831 SEQ ID NO: 1063 AAV variant 3353 WO2018071831 SEQ ID NO: 1064 AAV variant 3354 WO2018071831 SEQ ID NO: 1065 AAV variant 3355 WO2018071831 SEQ ID NO: 1066 AAV variant 3356 WO2018071831 SEQ ID NO: 1067 AAV variant 3357 WO2018071831 SEQ ID NO: 1068 AAV variant 3358 WO2018071831 SEQ ID NO: 1069 AAV variant 3359 WO2018071831 SEQ ID NO: 1070 AAV variant 3360 WO2018071831 SEQ ID NO: 1071 AAV variant 3361 WO2018071831 SEQ ID NO: 1072 AAV variant 3362 WO2018071831 SEQ ID NO: 1073 AAV variant 3363 WO2018071831 SEQ ID NO: 1074 AAV variant 3364 WO2018071831 SEQ ID NO: 1075 AAV variant 3365 WO2018071831 SEQ ID NO: 1076 AAV variant 3366 WO2018071831 SEQ ID NO: 1077 AAV variant 3367 WO2018071831 SEQ ID NO: 1078 AAV variant 3368 WO2018071831 SEQ ID NO: 1079 AAV variant 3369 WO2018071831 SEQ ID NO: 1080 AAV variant 3370 WO2018071831 SEQ ID NO: 1081 AAV variant 3371 WO2018071831 SEQ ID NO: 1082 AAV variant 3372 WO2018071831 SEQ ID NO: 1083 AAV variant 3373 WO2018071831 SEQ ID NO: 1084 AAV variant 3374 WO2018071831 SEQ ID NO: 1085 AAV variant 3375 WO2018071831 SEQ ID NO: 1086 AAV variant 3376 WO2018071831 SEQ ID NO: 1087 AAV variant 3377 WO2018071831 SEQ ID NO: 1088 AAV variant 3378 WO2018071831 SEQ ID NO: 1089 AAV variant 3379 WO2018071831 SEQ ID NO: 1090 AAV variant 3380 WO2018071831 SEQ ID NO: 1091 AAV variant 3381 WO2018071831 SEQ ID NO: 1092 AAV variant 3382 WO2018071831 SEQ ID NO: 1093 AAV variant 3383 WO2018071831 SEQ ID NO: 1094 AAV variant 3384 WO2018071831 SEQ ID NO: 1095 AAV variant 3385 WO2018071831 SEQ ID NO: 1096 AAV variant 3386 WO2018071831 SEQ ID NO: 1097 AAV variant 3387 WO2018071831 SEQ ID NO: 1098 AAV variant 3388 WO2018071831 SEQ ID NO: 1099 AAV variant 3389 WO2018071831 SEQ ID NO: 1100 AAV variant 3390 WO2018071831 SEQ ID NO: 1101 AAV variant 3391 WO2018071831 SEQ ID NO: 1102 AAV variant 3392 WO2018071831 SEQ ID NO: 1103 AAV variant 3393 WO2018071831 SEQ ID NO: 1104 AAV variant 3394 WO2018071831 SEQ ID NO: 1105 AAV variant 3395 WO2018071831 SEQ ID NO: 1106 AAV variant 3396 WO2018071831 SEQ ID NO: 1107 AAV variant 3397 WO2018071831 SEQ ID NO: 1108 AAV variant 3398 WO2018071831 SEQ ID NO: 1109 AAV variant 3399 WO2018071831 SEQ ID NO: 1110 AAV variant 3400 WO2018071831 SEQ ID NO: 1111 AAV variant 3401 WO2018071831 SEQ ID NO: 1112 AAV variant 3402 WO2018071831 SEQ ID NO: 1113 AAV variant 3403 WO2018071831 SEQ ID NO: 1114 AAV variant 3404 WO2018071831 SEQ ID NO: 1115 AAV variant 3405 WO2018071831 SEQ ID NO: 1116 AAV variant 3406 WO2018071831 SEQ ID NO: 1117 AAV variant 3407 WO2018071831 SEQ ID NO: 1118 AAV variant 3408 WO2018071831 SEQ ID NO: 1119 AAV variant 3409 WO2018071831 SEQ ID NO: 1120 AAV variant 3410 WO2018071831 SEQ ID NO: 1121 AAV variant 3411 WO2018071831 SEQ ID NO: 1122 AAV variant 3412 WO2018071831 SEQ ID NO: 1123 AAV variant 3413 WO2018071831 SEQ ID NO: 1124 AAV variant 3414 WO2018071831 SEQ ID NO: 1125 AAV variant 3415 WO2018071831 SEQ ID NO: 1126 AAV variant 3416 WO2018071831 SEQ ID NO: 1127 AAV variant 3417 WO2018071831 SEQ ID NO: 1128 AAV variant 3418 WO2018071831 SEQ ID NO: 1129 AAV variant 3419 WO2018071831 SEQ ID NO: 1130 AAV variant 3420 WO2018071831 SEQ ID NO: 1131 AAV variant 3421 WO2018071831 SEQ ID NO: 1132 AAV variant 3422 WO2018071831 SEQ ID NO: 1133 AAV variant 3423 WO2018071831 SEQ ID NO: 1134 AAV variant 3424 WO2018071831 SEQ ID NO: 1135 AAV variant 3425 WO2018071831 SEQ ID NO: 1136 AAV variant 3426 WO2018071831 SEQ ID NO: 1137 AAV variant 3427 WO2018071831 SEQ ID NO: 1138 AAV variant 3428 WO2018071831 SEQ ID NO: 1139 AAV variant 3429 WO2018071831 SEQ ID NO: 1140 AAV variant 3430 WO2018071831 SEQ ID NO: 1141 AAV variant 3431 WO2018071831 SEQ ID NO: 1142 AAV variant 3432 WO2018071831 SEQ ID NO: 1143 AAV variant 3433 WO2018071831 SEQ ID NO: 1144 AAV variant 3434 WO2018071831 SEQ ID NO: 1145 AAV variant 3435 WO2018071831 SEQ ID NO: 1146 AAV variant 3436 WO2018071831 SEQ ID NO: 1147 AAV variant 3437 WO2018071831 SEQ ID NO: 1148 AAV variant 3438 WO2018071831 SEQ ID NO: 1149 AAV variant 3439 WO2018071831 SEQ ID NO: 1150 AAV variant 3440 WO2018071831 SEQ ID NO: 1151 AAV variant 3441 WO2018071831 SEQ ID NO: 1152 AAV variant 3442 WO2018071831 SEQ ID NO: 1153 AAV variant 3443 WO2018071831 SEQ ID NO: 1154 AAV variant 3444 WO2018071831 SEQ ID NO: 1155 AAV variant 3445 WO2018071831 SEQ ID NO: 1156 AAV variant 3446 WO2018071831 SEQ ID NO: 1157 AAV variant 3447 WO2018071831 SEQ ID NO: 1158 AAV variant 3448 WO2018071831 SEQ ID NO: 1159 AAV variant 3449 WO2018071831 SEQ ID NO: 1160 AAV variant 3450 WO2018071831 SEQ ID NO: 1161 AAV variant 3451 WO2018071831 SEQ ID NO: 1162 AAV variant 3452 WO2018071831 SEQ ID NO: 1163 AAV variant 3453 WO2018071831 SEQ ID NO: 1164 AAV variant 3454 WO2018071831 SEQ ID NO: 1165 AAV variant 3455 WO2018071831 SEQ ID NO: 1166 AAV variant 3456 WO2018071831 SEQ ID NO: 1167 AAV variant 3457 WO2018071831 SEQ ID NO: 1168 AAV variant 3458 WO2018071831 SEQ ID NO: 1169 AAV variant 3459 WO2018071831 SEQ ID NO: 1170 AAV variant 3460 WO2018071831 SEQ ID NO: 1171 AAV variant 3461 WO2018071831 SEQ ID NO: 1172 AAV variant 3462 WO2018071831 SEQ ID NO: 1173 AAV variant 3463 WO2018071831 SEQ ID NO: 1174 AAV variant 3464 WO2018071831 SEQ ID NO: 1175 AAV variant 3465 WO2018071831 SEQ ID NO: 1176 AAV variant 3466 WO2018071831 SEQ ID NO: 1177 AAV variant 3467 WO2018071831 SEQ ID NO: 1178 AAV variant 3468 WO2018071831 SEQ ID NO: 1179 AAV variant 3469 WO2018071831 SEQ ID NO: 1180 AAV variant 3470 WO2018071831 SEQ ID NO: 1181 AAV variant 3471 WO2018071831 SEQ ID NO: 1182 AAV variant 3472 WO2018071831 SEQ ID NO: 1183 AAV variant 3473 WO2018071831 SEQ ID NO: 1184 AAV variant 3474 WO2018071831 SEQ ID NO: 1185 AAV variant 3475 WO2018071831 SEQ ID NO: 1186 AAV variant 3476 WO2018071831 SEQ ID NO: 1187 AAV variant 3477 WO2018071831 SEQ ID NO: 1188 AAV variant 3478 WO2018071831 SEQ ID NO: 1189 AAV variant 3479 WO2018071831 SEQ ID NO: 1190 AAV variant 3480 WO2018071831 SEQ ID NO: 1191 AAV variant 3481 WO2018071831 SEQ ID NO: 1192 AAV variant 3482 WO2018071831 SEQ ID NO: 1193 AAV variant 3483 WO2018071831 SEQ ID NO: 1194 AAV variant 3484 WO2018071831 SEQ ID NO: 1195 AAV variant 3485 WO2018071831 SEQ ID NO: 1196 AAV variant 3486 WO2018071831 SEQ ID NO: 1197 AAV variant 3487 WO2018071831 SEQ ID NO: 1198 AAV variant 3488 WO2018071831 SEQ ID NO: 1199 AAV variant 3489 WO2018071831 SEQ ID NO: 1200 AAV variant 3490 WO2018071831 SEQ ID NO: 1201 AAV variant 3491 WO2018071831 SEQ ID NO: 1202 AAV variant 3492 WO2018071831 SEQ ID NO: 1203 AAV variant 3493 WO2018071831 SEQ ID NO: 1204 AAV variant 3494 WO2018071831 SEQ ID NO: 1205 AAV variant 3495 WO2018071831 SEQ ID NO: 1206 AAV variant 3496 WO2018071831 SEQ ID NO: 1207 AAV variant 3497 WO2018071831 SEQ ID NO: 1208 AAV variant 3498 WO2018071831 SEQ ID NO: 1209 AAV variant 3499 WO2018071831 SEQ ID NO: 1210 AAV variant 3500 WO2018071831 SEQ ID NO: 1211 AAV variant 3501 WO2018071831 SEQ ID NO: 1212 AAV variant 3502 WO2018071831 SEQ ID NO: 1213 AAV variant 3503 WO2018071831 SEQ ID NO: 1214 AAV variant 3504 WO2018071831 SEQ ID NO: 1215 AAV variant 3505 WO2018071831 SEQ ID NO: 1216 AAV variant 3506 WO2018071831 SEQ ID NO: 1217 AAV variant 3507 WO2018071831 SEQ ID NO: 1218 AAV variant 3508 WO2018071831 SEQ ID NO: 1219 AAV variant 3509 WO2018071831 SEQ ID NO: 1220 AAV variant 3510 WO2018071831 SEQ ID NO: 1221 AAV variant 3511 WO2018071831 SEQ ID NO: 1222 AAV variant 3512 WO2018071831 SEQ ID NO: 1223 AAV variant 3513 WO2018071831 SEQ ID NO: 1224 AAV variant 3514 WO2018071831 SEQ ID NO: 1225 AAV variant 3515 WO2018071831 SEQ ID NO: 1226 AAV variant 3516 WO2018071831 SEQ ID NO: 1227 AAV variant 3517 WO2018071831 SEQ ID NO: 1228 AAV variant 3518 WO2018071831 SEQ ID NO: 1229 AAV variant 3519 WO2018071831 SEQ ID NO: 1230 AAV variant 3520 WO2018071831 SEQ ID NO: 1231 AAV variant 3521 WO2018071831 SEQ ID NO: 1232 AAV variant 3522 WO2018071831 SEQ ID NO: 1233 AAV variant 3523 WO2018071831 SEQ ID NO: 1234 AAV variant 3524 WO2018071831 SEQ ID NO: 1235 AAV variant 3525 WO2018071831 SEQ ID NO: 1236 AAV variant 3526 WO2018071831 SEQ ID NO: 1237 AAV variant 3527 WO2018071831 SEQ ID NO: 1238 AAV variant 3528 WO2018071831 SEQ ID NO: 1239 AAV variant 3529 WO2018071831 SEQ ID NO: 1240 AAV variant 3530 WO2018071831 SEQ ID NO: 1241 AAV variant 3531 WO2018071831 SEQ ID NO: 1242 AAV variant 3532 WO2018071831 SEQ ID NO: 1243 AAV variant 3533 WO2018071831 SEQ ID NO: 1244 AAV variant 3534 WO2018071831 SEQ ID NO: 1245 AAV variant 3535 WO2018071831 SEQ ID NO: 1246 AAV variant 3536 WO2018071831 SEQ ID NO: 1247 AAV variant 3537 WO2018071831 SEQ ID NO: 1248 AAV variant 3538 WO2018071831 SEQ ID NO: 1249 AAV variant 3539 WO2018071831 SEQ ID NO: 1250 AAV variant 3540 WO2018071831 SEQ ID NO: 1251 AAV variant 3541 WO2018071831 SEQ ID NO: 1252 AAV variant 3542 WO2018071831 SEQ ID NO: 1253 AAV variant 3543 WO2018071831 SEQ ID NO: 1254 AAV variant 3544 WO2018071831 SEQ ID NO: 1255 AAV variant 3545 WO2018071831 SEQ ID NO: 1256 AAV variant 3546 WO2018071831 SEQ ID NO: 1257 AAV variant 3547 WO2018071831 SEQ ID NO: 1258 AAV variant 3548 WO2018071831 SEQ ID NO: 1259 AAV variant 3549 WO2018071831 SEQ ID NO: 1260 AAV variant 3550 WO2018071831 SEQ ID NO: 1261 AAV variant 3551 WO2018071831 SEQ ID NO: 1262 AAV variant 3552 WO2018071831 SEQ ID NO: 1263 AAV variant 3553 WO2018071831 SEQ ID NO: 1264 AAV variant 3554 WO2018071831 SEQ ID NO: 1265 AAV variant 3555 WO2018071831 SEQ ID NO: 1266 AAV variant 3556 WO2018071831 SEQ ID NO: 1267 AAV variant 3557 WO2018071831 SEQ ID NO: 1268 AAV variant 3558 WO2018071831 SEQ ID NO: 1269 AAV variant 3559 WO2018071831 SEQ ID NO: 1270 AAV variant 3560 WO2018071831 SEQ ID NO: 1271 AAV variant 3561 WO2018071831 SEQ ID NO: 1272 AAV variant 3562 WO2018071831 SEQ ID NO: 1273 AAV variant 3563 WO2018071831 SEQ ID NO: 1274 AAV variant 3564 WO2018071831 SEQ ID NO: 1275 AAV variant 3565 WO2018071831 SEQ ID NO: 1276 AAV variant 3566 WO2018071831 SEQ ID NO: 1277 AAV variant 3567 WO2018071831 SEQ ID NO: 1278 AAV variant 3568 WO2018071831 SEQ ID NO: 1279 AAV variant 3569 WO2018071831 SEQ ID NO: 1280 AAV variant 3570 WO2018071831 SEQ ID NO: 1281 AAV variant 3571 WO2018071831 SEQ ID NO: 1282 AAV variant 3572 WO2018071831 SEQ ID NO: 1283 AAV variant 3573 WO2018071831 SEQ ID NO: 1284 AAV variant 3574 WO2018071831 SEQ ID NO: 1285 AAV variant 3575 WO2018071831 SEQ ID NO: 1286 AAV variant 3576 WO2018071831 SEQ ID NO: 1287 AAV variant 3577 WO2018071831 SEQ ID NO: 1288 AAV variant 3578 WO2018071831 SEQ ID NO: 1289 AAV variant 3579 WO2018071831 SEQ ID NO: 1290 AAV variant 3580 WO2018071831 SEQ ID NO: 1291 AAV variant 3581 WO2018071831 SEQ ID NO: 1292 AAV variant 3582 WO2018071831 SEQ ID NO: 1293 AAV variant 3583 WO2018071831 SEQ ID NO: 1294 AAV variant 3584 WO2018071831 SEQ ID NO: 1295 AAV variant 3585 WO2018071831 SEQ ID NO: 1296 AAV variant 3586 WO2018071831 SEQ ID NO: 1297 AAV variant 3587 WO2018071831 SEQ ID NO: 1298 AAV variant 3588 WO2018071831 SEQ ID NO: 1299 AAV variant 3589 WO2018071831 SEQ ID NO: 1300 AAV variant 3590 WO2018071831 SEQ ID NO: 1301 AAV variant 3591 WO2018071831 SEQ ID NO: 1302 AAV variant 3592 WO2018071831 SEQ ID NO: 1303 AAV variant 3593 WO2018071831 SEQ ID NO: 1304 AAV variant 3594 WO2018071831 SEQ ID NO: 1305 AAV variant 3595 WO2018071831 SEQ ID NO: 1306 AAV variant 3596 WO2018071831 SEQ ID NO: 1307 AAV variant 3597 WO2018071831 SEQ ID NO: 1308 AAV variant 3598 WO2018071831 SEQ ID NO: 1309 AAV variant 3599 WO2018071831 SEQ ID NO: 1310 AAV variant 3600 WO2018071831 SEQ ID NO: 1311 AAV variant 3601 WO2018071831 SEQ ID NO: 1312 AAV variant 3602 WO2018071831 SEQ ID NO: 1313 AAV variant 3603 WO2018071831 SEQ ID NO: 1314 AAV variant 3604 WO2018071831 SEQ ID NO: 1315 AAV variant 3605 WO2018071831 SEQ ID NO: 1316 AAV variant 3606 WO2018071831 SEQ ID NO: 1317 AAV variant 3607 WO2018071831 SEQ ID NO: 1318 AAV variant 3608 WO2018071831 SEQ ID NO: 1319 AAV variant 3609 WO2018071831 SEQ ID NO: 1320 AAV variant 3610 WO2018071831 SEQ ID NO: 1321 AAV variant 3611 WO2018071831 SEQ ID NO: 1322 AAV variant 3612 WO2018071831 SEQ ID NO: 1323 AAV variant 3613 WO2018071831 SEQ ID NO: 1324 AAV variant 3614 WO2018071831 SEQ ID NO: 1325 AAV variant 3615 WO2018071831 SEQ ID NO: 1326 AAV variant 3616 WO2018071831 SEQ ID NO: 1327 AAV variant 3617 WO2018071831 SEQ ID NO: 1328 AAV variant 3618 WO2018071831 SEQ ID NO: 1329 AAV variant 3619 WO2018071831 SEQ ID NO: 1330 AAV variant 3620 WO2018071831 SEQ ID NO: 1331 AAV variant 3621 WO2018071831 SEQ ID NO: 1332 AAV variant 3622 WO2018071831 SEQ ID NO: 1333 AAV variant 3623 WO2018071831 SEQ ID NO: 1334 AAV variant 3624 WO2018071831 SEQ ID NO: 1335 AAV variant 3625 WO2018071831 SEQ ID NO: 1336 AAV variant 3626 WO2018071831 SEQ ID NO: 1337 AAV variant 3627 WO2018071831 SEQ ID NO: 1338 AAV variant 3628 WO2018071831 SEQ ID NO: 1339 AAV variant 3629 WO2018071831 SEQ ID NO: 1340 AAV variant 3630 WO2018071831 SEQ ID NO: 1341 AAV variant 3631 WO2018071831 SEQ ID NO: 1342 AAV variant 3632 WO2018071831 SEQ ID NO: 1343 AAV variant 3633 WO2018071831 SEQ ID NO: 1344 AAV variant 3634 WO2018071831 SEQ ID NO: 1345 AAV variant 3635 WO2018071831 SEQ ID NO: 1346 AAV variant 3636 WO2018071831 SEQ ID NO: 1347 AAV variant 3637 WO2018071831 SEQ ID NO: 1348 AAV variant 3638 WO2018071831 SEQ ID NO: 1349 AAV variant 3639 WO2018071831 SEQ ID NO: 1350 AAV variant 3640 WO2018071831 SEQ ID NO: 1351 AAV variant 3641 WO2018071831 SEQ ID NO: 1352 AAV variant 3642 WO2018071831 SEQ ID NO: 1353 AAV variant 3643 WO2018071831 SEQ ID NO: 1354 AAV variant 3644 WO2018071831 SEQ ID NO: 1355 AAV variant 3645 WO2018071831 SEQ ID NO: 1356 AAV variant 3646 WO2018071831 SEQ ID NO: 1357 AAV variant 3647 WO2018071831 SEQ ID NO: 1358 AAV variant 3648 WO2018071831 SEQ ID NO: 1359 AAV variant 3649 WO2018071831 SEQ ID NO: 1360 AAV variant 3650 WO2018071831 SEQ ID NO: 1361 AAV variant 3651 WO2018071831 SEQ ID NO: 1362 AAV variant 3652 WO2018071831 SEQ ID NO: 1363 AAV variant 3653 WO2018071831 SEQ ID NO: 1364 AAV variant 3654 WO2018071831 SEQ ID NO: 1365 AAV variant 3655 WO2018071831 SEQ ID NO: 1366 AAV variant 3656 WO2018071831 SEQ ID NO: 1367 AAV variant 3657 WO2018071831 SEQ ID NO: 1368 AAV variant 3658 WO2018071831 SEQ ID NO: 1369 AAV variant 3659 WO2018071831 SEQ ID NO: 1370 AAV variant 3660 WO2018071831 SEQ ID NO: 1371 AAV variant 3661 WO2018071831 SEQ ID NO: 1372 AAV variant 3662 WO2018071831 SEQ ID NO: 1373 AAV variant 3663 WO2018071831 SEQ ID NO: 1374 AAV variant 3664 WO2018071831 SEQ ID NO: 1375 AAV variant 3665 WO2018071831 SEQ ID NO: 1376 AAV variant 3666 WO2018071831 SEQ ID NO: 1377 AAV variant 3667 WO2018071831 SEQ ID NO: 1378 AAV variant 3668 WO2018071831 SEQ ID NO: 1379 AAV variant 3669 WO2018071831 SEQ ID NO: 1380 AAV variant 3670 WO2018071831 SEQ ID NO: 1381 AAV variant 3671 WO2018071831 SEQ ID NO: 1382 AAV variant 3672 WO2018071831 SEQ ID NO: 1383 AAV variant 3673 WO2018071831 SEQ ID NO: 1384 AAV variant 3674 WO2018071831 SEQ ID NO: 1385 AAV variant 3675 WO2018071831 SEQ ID NO: 1386 AAV variant 3676 WO2018071831 SEQ ID NO: 1387 AAV variant 3677 WO2018071831 SEQ ID NO: 1388 AAV variant 3678 WO2018071831 SEQ ID NO: 1389 AAV variant 3679 WO2018071831 SEQ ID NO: 1390 AAV variant 3680 WO2018071831 SEQ ID NO: 1391 AAV variant 3681 WO2018071831 SEQ ID NO: 1392 AAV variant 3682 WO2018071831 SEQ ID NO: 1393 AAV variant 3683 WO2018071831 SEQ ID NO: 1394 AAV variant 3684 WO2018071831 SEQ ID NO: 1395 AAV variant 3685 WO2018071831 SEQ ID NO: 1396 AAV variant 3686 WO2018071831 SEQ ID NO: 1397 AAV variant 3687 WO2018071831 SEQ ID NO: 1398 AAV variant 3688 WO2018071831 SEQ ID NO: 1399 AAV variant 3689 WO2018071831 SEQ ID NO: 1400 AAV variant 3690 WO2018071831 SEQ ID NO: 1401 AAV variant 3691 WO2018071831 SEQ ID NO: 1402 AAV variant 3692 WO2018071831 SEQ ID NO: 1403 AAV variant 3693 WO2018071831 SEQ ID NO: 1404 AAV variant 3694 WO2018071831 SEQ ID NO: 1405 AAV variant 3695 WO2018071831 SEQ ID NO: 1406 AAV variant 3696 WO2018071831 SEQ ID NO: 1407 AAV variant 3697 WO2018071831 SEQ ID NO: 1408 AAV variant 3698 WO2018071831 SEQ ID NO: 1409 AAV variant 3699 WO2018071831 SEQ ID NO: 1410 AAV variant 3700 WO2018071831 SEQ ID NO: 1411 AAV variant 3701 WO2018071831 SEQ ID NO: 1412 AAV variant 3702 WO2018071831 SEQ ID NO: 1413 AAV variant 3703 WO2018071831 SEQ ID NO: 1414 AAV variant 3704 WO2018071831 SEQ ID NO: 1415 AAV variant 3705 WO2018071831 SEQ ID NO: 1416 AAV variant 3706 WO2018071831 SEQ ID NO: 1417 AAV variant 3707 WO2018071831 SEQ ID NO: 1418 AAV variant 3708 WO2018071831 SEQ ID NO: 1419 AAV variant 3709 WO2018071831 SEQ ID NO: 1420 AAV variant 3710 WO2018071831 SEQ ID NO: 1421 AAV variant 3711 WO2018071831 SEQ ID NO: 1422 AAV variant 3712 WO2018071831 SEQ ID NO: 1423 AAV variant 3713 WO2018071831 SEQ ID NO: 1424 AAV variant 3714 WO2018071831 SEQ ID NO: 1425 AAV variant 3715 WO2018071831 SEQ ID NO: 1426 AAV variant 3716 WO2018071831 SEQ ID NO: 1427 AAV variant 3717 WO2018071831 SEQ ID NO: 1428 AAV variant 3718 WO2018071831 SEQ ID NO: 1429 AAV variant 3719 WO2018071831 SEQ ID NO: 1430 AAV variant 3720 WO2018071831 SEQ ID NO: 1431 AAV variant 3721 WO2018071831 SEQ ID NO: 1432 AAV variant 3722 WO2018071831 SEQ ID NO: 1433 AAV variant 3723 WO2018071831 SEQ ID NO: 1434 AAV variant 3724 WO2018071831 SEQ ID NO: 1435 AAV variant 3725 WO2018071831 SEQ ID NO: 1436 AAV variant 3726 WO2018071831 SEQ ID NO: 1437 AAV variant 3727 WO2018071831 SEQ ID NO: 1438 AAV variant 3728 WO2018071831 SEQ ID NO: 1439 AAV variant 3729 WO2018071831 SEQ ID NO: 1440 AAV variant 3730 WO2018071831 SEQ ID NO: 1441 AAV variant 3731 WO2018071831 SEQ ID NO: 1442 AAV variant 3732 WO2018071831 SEQ ID NO: 1443 AAV variant 3733 WO2018071831 SEQ ID NO: 1444 AAV variant 3734 WO2018071831 SEQ ID NO: 1445 AAV variant 3735 WO2018071831 SEQ ID NO: 1446 AAV variant 3736 WO2018071831 SEQ ID NO: 1447 AAV variant 3737 WO2018071831 SEQ ID NO: 1448 AAV variant 3738 WO2018071831 SEQ ID NO: 1449 AAV variant 3739 WO2018071831 SEQ ID NO: 1450 AAV variant 3740 WO2018071831 SEQ ID NO: 1451 AAV variant 3741 WO2018071831 SEQ ID NO: 1452 AAV variant 3742 WO2018071831 SEQ ID NO: 1453 AAV variant 3743 WO2018071831 SEQ ID NO: 1454 AAV variant 3744 WO2018071831 SEQ ID NO: 1455 AAV variant 3745 WO2018071831 SEQ ID NO: 1456 AAV variant 3746 WO2018071831 SEQ ID NO: 1457 AAV variant 3747 WO2018071831 SEQ ID NO: 1458 AAV variant 3748 WO2018071831 SEQ ID NO: 1459 AAV variant 3749 WO2018071831 SEQ ID NO: 1460 AAV variant 3750 WO2018071831 SEQ ID NO: 1461 AAV variant 3751 WO2018071831 SEQ ID NO: 1462 AAV variant 3752 WO2018071831 SEQ ID NO: 1463 AAV variant 3753 WO2018071831 SEQ ID NO: 1464 AAV variant 3754 WO2018071831 SEQ ID NO: 1465 AAV variant 3755 WO2018071831 SEQ ID NO: 1466 AAV variant 3756 WO2018071831 SEQ ID NO: 1467 AAV variant 3757 WO2018071831 SEQ ID NO: 1468 AAV variant 3758 WO2018071831 SEQ ID NO: 1469 AAV variant 3759 WO2018071831 SEQ ID NO: 1470 AAV variant 3760 WO2018071831 SEQ ID NO: 1471 AAV variant 3761 WO2018071831 SEQ ID NO: 1472 AAV variant 3762 WO2018071831 SEQ ID NO: 1473 AAV variant 3763 WO2018071831 SEQ ID NO: 1474 AAV variant 3764 WO2018071831 SEQ ID NO: 1475 AAV variant 3765 WO2018071831 SEQ ID NO: 1476 AAV variant 3766 WO2018071831 SEQ ID NO: 1477 AAV variant 3767 WO2018071831 SEQ ID NO: 1478 AAV variant 3768 WO2018071831 SEQ ID NO: 1479 AAV variant 3769 WO2018071831 SEQ ID NO: 1480 AAV variant 3770 WO2018071831 SEQ ID NO: 1481 AAV variant 3771 WO2018071831 SEQ ID NO: 1482 AAV variant 3772 WO2018071831 SEQ ID NO: 1483 AAV variant 3773 WO2018071831 SEQ ID NO: 1484 AAV variant 3774 WO2018071831 SEQ ID NO: 1485 AAV variant 3775 WO2018071831 SEQ ID NO: 1486 AAV variant 3776 WO2018071831 SEQ ID NO: 1487 AAV variant 3777 WO2018071831 SEQ ID NO: 1488 AAV variant 3778 WO2018071831 SEQ ID NO: 1489 AAV variant 3779 WO2018071831 SEQ ID NO: 1490 AAV variant 3780 WO2018071831 SEQ ID NO: 1491 AAV variant 3781 WO2018071831 SEQ ID NO: 1492 AAV variant 3782 WO2018071831 SEQ ID NO: 1493 AAV variant 3783 WO2018071831 SEQ ID NO: 1494 AAV variant 3784 WO2018071831 SEQ ID NO: 1495 AAV variant 3785 WO2018071831 SEQ ID NO: 1496 AAV variant 3786 WO2018071831 SEQ ID NO: 1497 AAV variant 3787 WO2018071831 SEQ ID NO: 1498 AAV variant 3788 WO2018071831 SEQ ID NO: 1499 AAV variant 3789 WO2018071831 SEQ ID NO: 1500 AAV variant 3790 WO2018071831 SEQ ID NO: 1501 AAV variant 3791 WO2018071831 SEQ ID NO: 1502 AAV variant 3792 WO2018071831 SEQ ID NO: 1503 AAV variant 3793 WO2018071831 SEQ ID NO: 1504 AAV variant 3794 WO2018071831 SEQ ID NO: 1505 AAV variant 3795 WO2018071831 SEQ ID NO: 1506 AAV variant 3796 WO2018071831 SEQ ID NO: 1507 AAV variant 3797 WO2018071831 SEQ ID NO: 1508 AAV variant 3798 WO2018071831 SEQ ID NO: 1509 AAV variant 3799 WO2018071831 SEQ ID NO: 1510 AAV variant 3800 WO2018071831 SEQ ID NO: 1511 AAV variant 3801 WO2018071831 SEQ ID NO: 1512 AAV variant 3802 WO2018071831 SEQ ID NO: 1513 AAV variant 3803 WO2018071831 SEQ ID NO: 1514 AAV variant 3804 WO2018071831 SEQ ID NO: 1515 AAV variant 3805 WO2018071831 SEQ ID NO: 1516 AAV variant 3806 WO2018071831 SEQ ID NO: 1517 AAV variant 3807 WO2018071831 SEQ ID NO: 1518 AAV variant 3808 WO2018071831 SEQ ID NO: 1519 AAV variant 3809 WO2018071831 SEQ ID NO: 1520 AAV variant 3810 WO2018071831 SEQ ID NO: 1521 AAV variant 3811 WO2018071831 SEQ ID NO: 1522 AAV variant 3812 WO2018071831 SEQ ID NO: 1523 AAV variant 3813 WO2018071831 SEQ ID NO: 1524 AAV variant 3814 WO2018071831 SEQ ID NO: 1525 AAV variant 3815 WO2018071831 SEQ ID NO: 1526 AAV variant 3816 WO2018071831 SEQ ID NO: 1527 AAV variant 3817 WO2018071831 SEQ ID NO: 1528 AAV variant 3818 WO2018071831 SEQ ID NO: 1529 AAV variant 3819 WO2018071831 SEQ ID NO: 1530 AAV variant 3820 WO2018071831 SEQ ID NO: 1531 AAV variant 3821 WO2018071831 SEQ ID NO: 1532 AAV variant 3822 WO2018071831 SEQ ID NO: 1533 AAV variant 3823 WO2018071831 SEQ ID NO: 1534 AAV variant 3824 WO2018071831 SEQ ID NO: 1535 AAV variant 3825 WO2018071831 SEQ ID NO: 1536 AAV variant 3826 WO2018071831 SEQ ID NO: 1537 AAV variant 3827 WO2018071831 SEQ ID NO: 1538 AAV variant 3828 WO2018071831 SEQ ID NO: 1539 AAV variant 3829 WO2018071831 SEQ ID NO: 1540 AAV variant 3830 WO2018071831 SEQ ID NO: 1541 AAV variant 3831 WO2018071831 SEQ ID NO: 1542 AAV variant 3832 WO2018071831 SEQ ID NO: 1543 AAV variant 3833 WO2018071831 SEQ ID NO: 1544 AAV variant 3834 WO2018071831 SEQ ID NO: 1545 AAV variant 3835 WO2018071831 SEQ ID NO: 1546 AAV variant 3836 WO2018071831 SEQ ID NO: 1547 AAV variant 3837 WO2018071831 SEQ ID NO: 1548 AAV variant 3838 WO2018071831 SEQ ID NO: 1549 AAV variant 3839 WO2018071831 SEQ ID NO: 1550 AAV variant 3840 WO2018071831 SEQ ID NO: 1551 AAV variant 3841 WO2018071831 SEQ ID NO: 1552 AAV variant 3842 WO2018071831 SEQ ID NO: 1553 AAV variant 3843 WO2018071831 SEQ ID NO: 1554 AAV variant 3844 WO2018071831 SEQ ID NO: 1555 AAV variant 3845 WO2018071831 SEQ ID NO: 1556 AAV variant 3846 WO2018071831 SEQ ID NO: 1557 AAV variant 3847 WO2018071831 SEQ ID NO: 1558 AAV variant 3848 WO2018071831 SEQ ID NO: 1559 AAV variant 3849 WO2018071831 SEQ ID NO: 1560 AAV variant 3850 WO2018071831 SEQ ID NO: 1561 AAV variant 3851 WO2018071831 SEQ ID NO: 1562 AAV variant 3852 WO2018071831 SEQ ID NO: 1563 AAV variant 3853 WO2018071831 SEQ ID NO: 1564 AAV variant 3854 WO2018071831 SEQ ID NO: 1565 AAV variant 3855 WO2018071831 SEQ ID NO: 1566 AAV variant 3856 WO2018071831 SEQ ID NO: 1567 AAV variant 3857 WO2018071831 SEQ ID NO: 1568 AAV variant 3858 WO2018071831 SEQ ID NO: 1569 AAV variant 3859 WO2018071831 SEQ ID NO: 1570 AAV variant 3860 WO2018071831 SEQ ID NO: 1571 AAV variant 3861 WO2018071831 SEQ ID NO: 1572 AAV variant 3862 WO2018071831 SEQ ID NO: 1573 AAV variant 3863 WO2018071831 SEQ ID NO: 1574 AAV variant 3864 WO2018071831 SEQ ID NO: 1575 AAV variant 3865 WO2018071831 SEQ ID NO: 1576 AAV variant 3866 WO2018071831 SEQ ID NO: 1577 AAV variant 3867 WO2018071831 SEQ ID NO: 1578 AAV variant 3868 WO2018071831 SEQ ID NO: 1579 AAV variant 3869 WO2018071831 SEQ ID NO: 1580 AAV variant 3870 WO2018071831 SEQ ID NO: 1581 AAV variant 3871 WO2018071831 SEQ ID NO: 1582 AAV variant 3872 WO2018071831 SEQ ID NO: 1583 AAV variant 3873 WO2018071831 SEQ ID NO: 1584 AAV variant 3874 WO2018071831 SEQ ID NO: 1585 AAV variant 3875 WO2018071831 SEQ ID NO: 1586 AAV variant 3876 WO2018071831 SEQ ID NO: 1587 AAV variant 3877 WO2018071831 SEQ ID NO: 1588 AAV variant 3878 WO2018071831 SEQ ID NO: 1589 AAV variant 3879 WO2018071831 SEQ ID NO: 1590 AAV variant 3880 WO2018071831 SEQ ID NO: 1591 AAV variant 3881 WO2018071831 SEQ ID NO: 1592 AAV variant 3882 WO2018071831 SEQ ID NO: 1593 AAV variant 3883 WO2018071831 SEQ ID NO: 1594 AAV variant 3884 WO2018071831 SEQ ID NO: 1595 AAV variant 3885 WO2018071831 SEQ ID NO: 1596 AAV variant 3886 WO2018071831 SEQ ID NO: 1597 AAV variant 3887 WO2018071831 SEQ ID NO: 1598 AAV variant 3888 WO2018071831 SEQ ID NO: 1599 AAV variant 3889 WO2018071831 SEQ ID NO: 1600 AAV variant 3890 WO2018071831 SEQ ID NO: 1601 AAV variant 3891 WO2018071831 SEQ ID NO: 1602 AAV variant 3892 WO2018071831 SEQ ID NO: 1603 AAV variant 3893 WO2018071831 SEQ ID NO: 1604 AAV variant 3894 WO2018071831 SEQ ID NO: 1605 AAV variant 3895 WO2018071831 SEQ ID NO: 1606 AAV variant 3896 WO2018071831 SEQ ID NO: 1607 AAV variant 3897 WO2018071831 SEQ ID NO: 1608 AAV variant 3898 WO2018071831 SEQ ID NO: 1609 AAV variant 3899 WO2018071831 SEQ ID NO: 1610 AAV variant 3900 WO2018071831 SEQ ID NO: 1611 AAV variant 3901 WO2018071831 SEQ ID NO: 1612 AAV variant 3902 WO2018071831 SEQ ID NO: 1613 AAV variant 3903 WO2018071831 SEQ ID NO: 1614 AAV variant 3904 WO2018071831 SEQ ID NO: 1615 AAV variant 3905 WO2018071831 SEQ ID NO: 1616 AAV variant 3906 WO2018071831 SEQ ID NO: 1617 AAV variant 3907 WO2018071831 SEQ ID NO: 1618 AAV variant 3908 WO2018071831 SEQ ID NO: 1619 AAV variant 3909 WO2018071831 SEQ ID NO: 1620 AAV variant 3910 WO2018071831 SEQ ID NO: 1621 AAV variant 3911 WO2018071831 SEQ ID NO: 1622 AAV variant 3912 WO2018071831 SEQ ID NO: 1623 AAV variant 3913 WO2018071831 SEQ ID NO: 1624 AAV variant 3914 WO2018071831 SEQ ID NO: 1625 AAV variant 3915 WO2018071831 SEQ ID NO: 1626 AAV variant 3916 WO2018071831 SEQ ID NO: 1627 AAV variant 3917 WO2018071831 SEQ ID NO: 1628 AAV variant 3918 WO2018071831 SEQ ID NO: 1629 AAV variant 3919 WO2018071831 SEQ ID NO: 1630 AAV variant 3920 WO2018071831 SEQ ID NO: 1631 AAV variant 3921 WO2018071831 SEQ ID NO: 1632 AAV variant 3922 WO2018071831 SEQ ID NO: 1633 AAV variant 3923 WO2018071831 SEQ ID NO: 1634 AAV variant 3924 WO2018071831 SEQ ID NO: 1635 AAV variant 3925 WO2018071831 SEQ ID NO: 1636 AAV variant 3926 WO2018071831 SEQ ID NO: 1637 AAV variant 3927 WO2018071831 SEQ ID NO: 1638 AAV variant 3928 WO2018071831 SEQ ID NO: 1639 AAV variant 3929 WO2018071831 SEQ ID NO: 1640 AAV variant 3930 WO2018071831 SEQ ID NO: 1641 AAV variant 3931 WO2018071831 SEQ ID NO: 1642 AAV variant 3932 WO2018071831 SEQ ID NO: 1643 AAV variant 3933 WO2018071831 SEQ ID NO: 1644 AAV variant 3934 WO2018071831 SEQ ID NO: 1645 AAV variant 3935 WO2018071831 SEQ ID NO: 1646 AAV variant 3936 WO2018071831 SEQ ID NO: 1647 AAV variant 3937 WO2018071831 SEQ ID NO: 1648 AAV variant 3938 WO2018071831 SEQ ID NO: 1649 AAV variant 3939 WO2018071831 SEQ ID NO: 1650 AAV variant 3940 WO2018071831 SEQ ID NO: 1651 AAV variant 3941 WO2018071831 SEQ ID NO: 1652 AAV variant 3942 WO2018071831 SEQ ID NO: 1653 AAV variant 3943 WO2018071831 SEQ ID NO: 1654 AAV variant 3944 WO2018071831 SEQ ID NO: 1655 AAV variant 3945 WO2018071831 SEQ ID NO: 1656 AAV variant 3946 WO2018071831 SEQ ID NO: 1657 AAV variant 3947 WO2018071831 SEQ ID NO: 1658 AAV variant 3948 WO2018071831 SEQ ID NO: 1659 AAV variant 3949 WO2018071831 SEQ ID NO: 1660 AAV variant 3950 WO2018071831 SEQ ID NO: 1661 AAV variant 3951 WO2018071831 SEQ ID NO: 1662 AAV variant 3952 WO2018071831 SEQ ID NO: 1663 AAV variant 3953 WO2018071831 SEQ ID NO: 1664 AAV variant 3954 WO2018071831 SEQ ID NO: 1665 AAV variant 3955 WO2018071831 SEQ ID NO: 1666 AAV variant 3956 WO2018071831 SEQ ID NO: 1667 AAV variant 3957 WO2018071831 SEQ ID NO: 1668 AAV variant 3958 WO2018071831 SEQ ID NO: 1669 AAV variant 3959 WO2018071831 SEQ ID NO: 1670 AAV variant 3960 WO2018071831 SEQ ID NO: 1671 AAV variant 3961 WO2018071831 SEQ ID NO: 1672 AAV variant 3962 WO2018071831 SEQ ID NO: 1673 AAV variant 3963 WO2018071831 SEQ ID NO: 1674 AAV variant 3964 WO2018071831 SEQ ID NO: 1675 AAV variant 3965 WO2018071831 SEQ ID NO: 1676 AAV variant 3966 WO2018071831 SEQ ID NO: 1677 AAV variant 3967 WO2018071831 SEQ ID NO: 1678 AAV variant 3968 WO2018071831 SEQ ID NO: 1679 AAV variant 3969 WO2018071831 SEQ ID NO: 1680 AAV variant 3970 WO2018071831 SEQ ID NO: 1681 AAV variant 3971 WO2018071831 SEQ ID NO: 1682 AAV variant 3972 WO2018071831 SEQ ID NO: 1683 AAV variant 3973 WO2018071831 SEQ ID NO: 1684 AAV variant 3974 WO2018071831 SEQ ID NO: 1685 AAV variant 3975 WO2018071831 SEQ ID NO: 1686 AAV variant 3976 WO2018071831 SEQ ID NO: 1687 AAV variant 3977 WO2018071831 SEQ ID NO: 1688 AAV variant 3978 WO2018071831 SEQ ID NO: 1689 AAV variant 3979 WO2018071831 SEQ ID NO: 1690 AAV variant 3980 WO2018071831 SEQ ID NO: 1691 AAV variant 3981 WO2018071831 SEQ ID NO: 1692 AAV variant 3982 WO2018071831 SEQ ID NO: 1693 AAV variant 3983 WO2018071831 SEQ ID NO: 1694 AAV variant 3984 WO2018071831 SEQ ID NO: 1695 AAV variant 3985 WO2018071831 SEQ ID NO: 1696 AAV variant 3986 WO2018071831 SEQ ID NO: 1697 AAV variant 3987 WO2018071831 SEQ ID NO: 1698 AAV variant 3988 WO2018071831 SEQ ID NO: 1699 AAV variant 3989 WO2018071831 SEQ ID NO: 1700 AAV variant 3990 WO2018071831 SEQ ID NO: 1701 AAV variant 3991 WO2018071831 SEQ ID NO: 1702 AAV variant 3992 WO2018071831 SEQ ID NO: 1703 AAV variant 3993 WO2018071831 SEQ ID NO: 1704 AAV variant 3994 WO2018071831 SEQ ID NO: 1705 AAV variant 3995 WO2018071831 SEQ ID NO: 1706 AAV variant 3996 WO2018071831 SEQ ID NO: 1707 AAV variant 3997 WO2018071831 SEQ ID NO: 1708 AAV variant 3998 WO2018071831 SEQ ID NO: 1709 AAV variant 3999 WO2018071831 SEQ ID NO: 1710 AAV variant 4000 WO2018071831 SEQ ID NO: 1711 AAV variant 4001 WO2018071831 SEQ ID NO: 1712 AAV variant 4002 WO2018071831 SEQ ID NO: 1713 AAV variant 4003 WO2018071831 SEQ ID NO: 1714 AAV variant 4004 WO2018071831 SEQ ID NO: 1715 AAV variant 4005 WO2018071831 SEQ ID NO: 1716 AAV variant 4006 WO2018071831 SEQ ID NO: 1717 AAV variant 4007 WO2018071831 SEQ ID NO: 1718 AAV2 variant 4008 WO2018071831 SEQ ID NO: 1726 AAV2 variant 4009 WO2018071831 SEQ ID NO: 1727 AAV2 variant 4010 WO2018071831 SEQ ID NO: 1728 AAV2 variant 4011 WO2018071831 SEQ ID NO: 1729 AAV2 variant 4012 WO2018071831 SEQ ID NO: 1730 AAV2 variant 4013 WO2018071831 SEQ ID NO: 1731 AAV2 variant 4014 WO2018071831 SEQ ID NO: 1732 AAV2 variant 4015 WO2018071831 SEQ ID NO: 1733 AAV2 variant 4016 WO2018071831 SEQ ID NO: 1734 AAV2 variant 4017 WO2018071831 SEQ ID NO: 1735 AAV2 variant 4018 WO2018071831 SEQ ID NO: 1736 AAV2 variant 4019 WO2018071831 SEQ ID NO: 1737 AAV2 variant 4020 WO2018071831 SEQ ID NO: 1738 AAV2 variant 4021 WO2018071831 SEQ ID NO: 1739 AAV2 variant 4022 WO2018071831 SEQ ID NO: 1740 AAV2 variant 4023 WO2018071831 SEQ ID NO: 1741 AAV2 variant 4024 WO2018071831 SEQ ID NO: 1742 AAV2 variant 4025 WO2018071831 SEQ ID NO: 1743 AAV2 variant 4026 WO2018071831 SEQ ID NO: 1744 AAV2 variant 4027 WO2018071831 SEQ ID NO: 1745 AAV2 variant 4028 WO2018071831 SEQ ID NO: 1746 AAV2 variant 4029 WO2018071831 SEQ ID NO: 1747 AAV2 variant 4030 WO2018071831 SEQ ID NO: 1748 AAV2 variant 4031 WO2018071831 SEQ ID NO: 1749 AAV2 variant 4032 WO2018071831 SEQ ID NO: 1750 AAV2 variant 4033 WO2018071831 SEQ ID NO: 1751 AAV2 variant 4034 WO2018071831 SEQ ID NO: 1752 AAV2 variant 4035 WO2018071831 SEQ ID NO: 1753 AAV2 variant 4036 WO2018071831 SEQ ID NO: 1754 AAV2 variant 4037 WO2018071831 SEQ ID NO: 1755 AAV2 variant 4038 WO2018071831 SEQ ID NO: 1756 AAV2 variant 4039 WO2018071831 SEQ ID NO: 1757 AAV2 variant 4040 WO2018071831 SEQ ID NO: 1758 AAV2 variant 4041 WO2018071831 SEQ ID NO: 1759 AAV2 variant 4042 WO2018071831 SEQ ID NO: 1760 AAV2 variant 4043 WO2018071831 SEQ ID NO: 1761 AAV2 variant 4044 WO2018071831 SEQ ID NO: 1762 AAV2 variant 4045 WO2018071831 SEQ ID NO: 1763 AAV2 variant 4046 WO2018071831 SEQ ID NO: 1764 AAV2 variant 4047 WO2018071831 SEQ ID NO: 1765 AAV2 variant 4048 WO2018071831 SEQ ID NO: 1766 AAV2 variant 4049 WO2018071831 SEQ ID NO: 1767 AAV2 variant 4050 WO2018071831 SEQ ID NO: 1768 AAV2 variant 4051 WO2018071831 SEQ ID NO: 1769 AAV2 variant 4052 WO2018071831 SEQ ID NO: 1770 AAV2 variant 4053 WO2018071831 SEQ ID NO: 1771 AAV2 variant 4054 WO2018071831 SEQ ID NO: 1772 AAV2 variant 4055 WO2018071831 SEQ ID NO: 1773 AAV2 variant 4056 WO2018071831 SEQ ID NO: 1774 AAV2 variant 4057 WO2018071831 SEQ ID NO: 1775 AAV2 variant 4058 WO2018071831 SEQ ID NO: 1776 AAV2 variant 4059 WO2018071831 SEQ ID NO: 1777 AAV2 variant 4060 WO2018071831 SEQ ID NO: 1778 AAV2 variant 4061 WO2018071831 SEQ ID NO: 1779 AAV2 variant 4062 WO2018071831 SEQ ID NO: 1780 AAV2 variant 4063 WO2018071831 SEQ ID NO: 1781 AAV2 variant 4064 WO2018071831 SEQ ID NO: 1782 AAV2 variant 4065 WO2018071831 SEQ ID NO: 1783 AAV2 variant 4066 WO2018071831 SEQ ID NO: 1784 AAV2 variant 4067 WO2018071831 SEQ ID NO: 1785 AAV2 variant 4068 WO2018071831 SEQ ID NO: 1786 AAV2 variant 4069 WO2018071831 SEQ ID NO: 1787 AAV2 variant 4070 WO2018071831 SEQ ID NO: 1788 AAV2 variant 4071 WO2018071831 SEQ ID NO: 1789 AAV2 variant 4072 WO2018071831 SEQ ID NO: 1790 AAV2 variant 4073 WO2018071831 SEQ ID NO: 1791 AAV2 variant 4074 WO2018071831 SEQ ID NO: 1792 AAV2 variant 4075 WO2018071831 SEQ ID NO: 1793 AAV2 variant 4076 WO2018071831 SEQ ID NO: 1794 AAV2 variant 4077 WO2018071831 SEQ ID NO: 1795 AAV2 variant 4078 WO2018071831 SEQ ID NO: 1796 AAV2 variant 4079 WO2018071831 SEQ ID NO: 1797 AAV2 variant 4080 WO2018071831 SEQ ID NO: 1798 AAV2 variant 4081 WO2018071831 SEQ ID NO: 1799 AAV2 variant 4082 WO2018071831 SEQ ID NO: 1800 AAV2 variant 4083 WO2018071831 SEQ ID NO: 1801 AAV2 variant 4084 WO2018071831 SEQ ID NO: 1802 AAV2 variant 4085 WO2018071831 SEQ ID NO: 1803 AAV2 variant 4086 WO2018071831 SEQ ID NO: 1804 AAV2 variant 4087 WO2018071831 SEQ ID NO: 1805 AAV2 variant 4088 WO2018071831 SEQ ID NO: 1806 AAV2 variant 4089 WO2018071831 SEQ ID NO: 1807 AAV2 variant 4090 WO2018071831 SEQ ID NO: 1808 AAV2 variant 4091 WO2018071831 SEQ ID NO: 1809 AAV2 variant 4092 WO2018071831 SEQ ID NO: 1810 AAV2 variant 4093 WO2018071831 SEQ ID NO: 1811 AAV2 variant 4094 WO2018071831 SEQ ID NO: 1812 AAV2 variant 4095 WO2018071831 SEQ ID NO: 1813 AAV2 variant 4096 WO2018071831 SEQ ID NO: 1814 AAV2/3 variant 4097 WO2018071831 SEQ ID NO: 1815 AAV2/3 variant 4098 WO2018071831 SEQ ID NO: 1816 AAV2/3 variant 4099 WO2018071831 SEQ ID NO: 1817 AAV2/3 variant 4100 WO2018071831 SEQ ID NO: 1818 AAV2/3 variant 4101 WO2018071831 SEQ ID NO: 1819 AAV2/3 variant 4102 WO2018071831 SEQ ID NO: 1820 AAV2/3 variant 4103 WO2018071831 SEQ ID NO: 1821 AAV2/3 variant 4104 WO2018071831 SEQ ID NO: 1822 AAV2/3 variant 4105 WO2018071831 SEQ ID NO: 1823 AAV2/3 variant 4106 WO2018071831 SEQ ID NO: 1824 AAV2/3 variant 4107 WO2018071831 SEQ ID NO: 1825 AAV2/3 variant 4108 WO2018071831 SEQ ID NO: 1826 AAV2/3 variant 4109 WO2018071831 SEQ ID NO: 1827 AAV2/3 variant 4110 WO2018071831 SEQ ID NO: 1828 AAV2/3 variant 4111 WO2018071831 SEQ ID NO: 1829 AAV2/3 variant 4112 WO2018071831 SEQ ID NO: 1830 AAV2/3 variant 4113 WO2018071831 SEQ ID NO: 1831 AAV2/3 variant 4114 WO2018071831 SEQ ID NO: 1832 AAV2/3 variant 4115 WO2018071831 SEQ ID NO: 1833 AAV2/3 variant 4116 WO2018071831 SEQ ID NO: 1834 AAV2/3 variant 4117 WO2018071831 SEQ ID NO: 1835 AAV2/3 variant 4118 WO2018071831 SEQ ID NO: 1836 AAV2/3 variant 4119 WO2018071831 SEQ ID NO: 1837 AAV2/3 variant 4120 WO2018071831 SEQ ID NO: 1838 AAV2/3 variant 4121 WO2018071831 SEQ ID NO: 1839 AAV2/3 variant 4122 WO2018071831 SEQ ID NO: 1840 AAV2/3 variant 4123 WO2018071831 SEQ ID NO: 1841 AAV2/3 variant 4124 WO2018071831 SEQ ID NO: 1842 AAV2/3 variant 4125 WO2018071831 SEQ ID NO: 1843 AAV2/3 variant 4126 WO2018071831 SEQ ID NO: 1844 AAV2/3 variant 4127 WO2018071831 SEQ ID NO: 1845 AAV2/3 variant 4128 WO2018071831 SEQ ID NO: 1846 AAV2/3 variant 4129 WO2018071831 SEQ ID NO: 1847 AAV2/3 variant 4130 WO2018071831 SEQ ID NO: 1848 AAV2/3 variant 4131 WO2018071831 SEQ ID NO: 1849 AAV2/3 variant 4132 WO2018071831 SEQ ID NO: 1850 AAV2/3 variant 4133 WO2018071831 SEQ ID NO: 1851 AAV2/3 variant 4134 WO2018071831 SEQ ID NO: 1852 AAV2/3 variant 4135 WO2018071831 SEQ ID NO: 1853 AAV2/3 variant 4136 WO2018071831 SEQ ID NO: 1854 AAV2/3 variant 4137 WO2018071831 SEQ ID NO: 1855 AAV2/3 variant 4138 WO2018071831 SEQ ID NO: 1856 AAV2/3 variant 4139 WO2018071831 SEQ ID NO: 1857 AAV2/3 variant 4140 WO2018071831 SEQ ID NO: 1858 AAV2/3 variant 4141 WO2018071831 SEQ ID NO: 1859 AAV2/3 variant 4142 WO2018071831 SEQ ID NO: 1860 AAV2/3 variant 4143 WO2018071831 SEQ ID NO: 1861 AAV2/3 variant 4144 WO2018071831 SEQ ID NO: 1862 AAV2/3 variant 4145 WO2018071831 SEQ ID NO: 1863 AAV2/3 variant 4146 WO2018071831 SEQ ID NO: 1864 AAV2/3 variant 4147 WO2018071831 SEQ ID NO: 1865 AAV2/3 variant 4148 WO2018071831 SEQ ID NO: 1866 AAV2/3 variant 4149 WO2018071831 SEQ ID NO: 1867 AAV2/3 variant 4150 WO2018071831 SEQ ID NO: 1868 AAV2/3 variant 4151 WO2018071831 SEQ ID NO: 1869 AAV2/3 variant 4152 WO2018071831 SEQ ID NO: 1870 AAV2/3 variant 4153 WO2018071831 SEQ ID NO: 1871 AAV2/3 variant 4154 WO2018071831 SEQ ID NO: 1872 AAV2/3 variant 4155 WO2018071831 SEQ ID NO: 1873 AAV2/3 variant 4156 WO2018071831 SEQ ID NO: 1874 AAV2/3 variant 4157 WO2018071831 SEQ ID NO: 1875 AAV2/3 variant 4158 WO2018071831 SEQ ID NO: 1876 AAV2/3 variant 4159 WO2018071831 SEQ ID NO: 1877 AAV2/3 variant 4160 WO2018071831 SEQ ID NO: 1878 AAV2/3 variant 4161 WO2018071831 SEQ ID NO: 1879 AAV2/3 variant 4162 WO2018071831 SEQ ID NO: 1880 AAV2/3 variant 4163 WO2018071831 SEQ ID NO: 1881 AAV2/3 variant 4164 WO2018071831 SEQ ID NO: 1882 AAV2/3 variant 4165 WO2018071831 SEQ ID NO: 1883 AAV2/3 variant 4166 WO2018071831 SEQ ID NO: 1884 AAV2/3 variant 4167 WO2018071831 SEQ ID NO: 1885 AAV2/3 variant 4168 WO2018071831 SEQ ID NO: 1886 AAV2/3 variant 4169 WO2018071831 SEQ ID NO: 1887 AAV2/3 variant 4170 WO2018071831 SEQ ID NO: 1888 AAV2/3 variant 4171 WO2018071831 SEQ ID NO: 1889 AAV2/3 variant 4172 WO2018071831 SEQ ID NO: 1890 AAV2/3 variant 4173 WO2018071831 SEQ ID NO: 1891 AAV2/3 variant 4174 WO2018071831 SEQ ID NO: 1892 AAV2/3 variant 4175 WO2018071831 SEQ ID NO: 1893 AAV2/3 variant 4176 WO2018071831 SEQ ID NO: 1894 AAV2/3 variant 4177 WO2018071831 SEQ ID NO: 1895 AAV2/3 variant 4178 WO2018071831 SEQ ID NO: 1896 AAV2/3 variant 4179 WO2018071831 SEQ ID NO: 1897 AAV2/3 variant 4180 WO2018071831 SEQ ID NO: 1898 AAV2/3 variant 4181 WO2018071831 SEQ ID NO: 1899 AAV2/3 variant 4182 WO2018071831 SEQ ID NO: 1900 AAV2/3 variant 4183 WO2018071831 SEQ ID NO: 1901 AAV2/3 variant 4184 WO2018071831 SEQ ID NO: 1902 AAV2/3 variant 4185 WO2018071831 SEQ ID NO: 1903 AAV2/3 variant 4186 WO2018071831 SEQ ID NO: 1904 AAV2/3 variant 4187 WO2018071831 SEQ ID NO: 1905 AAV2/3 variant 4188 WO2018071831 SEQ ID NO: 1906 AAV2/3 variant 4189 WO2018071831 SEQ ID NO: 1907 AAV2/3 variant 4190 WO2018071831 SEQ ID NO: 1908 AAV2/3 variant 4191 WO2018071831 SEQ ID NO: 1909 AAV2/3 variant 4192 WO2018071831 SEQ ID NO: 1910 AAV2/3 variant 4193 WO2018071831 SEQ ID NO: 1911 AAV2/3 variant 4194 WO2018071831 SEQ ID NO: 1912 AAV2/3 variant 4195 WO2018071831 SEQ ID NO: 1913 AAV2/3 variant 4196 WO2018071831 SEQ ID NO: 1914 AAV2/3 variant 4197 WO2018071831 SEQ ID NO: 1915 AAV2/3 variant 4198 WO2018071831 SEQ ID NO: 1916 AAV2/3 variant 4199 WO2018071831 SEQ ID NO: 1917 AAV2/3 variant 4200 WO2018071831 SEQ ID NO: 1918 AAV2/3 variant 4201 WO2018071831 SEQ ID NO: 1919 AAV2/3 variant 4202 WO2018071831 SEQ ID NO: 1920 AAV2/3 variant 4203 WO2018071831 SEQ ID NO: 1921 AAV2/3 variant 4204 WO2018071831 SEQ ID NO: 1922 AAV2/3 variant 4205 WO2018071831 SEQ ID NO: 1923 AAV2/3 variant 4206 WO2018071831 SEQ ID NO: 1924 AAV2/3 variant 4207 WO2018071831 SEQ ID NO: 1925 AAV2/3 variant 4208 WO2018071831 SEQ ID NO: 1926 AAV2/3 variant 4209 WO2018071831 SEQ ID NO: 1927 AAV2/3 variant 4210 WO2018071831 SEQ ID NO: 1928 AAV2/3 variant 4211 WO2018071831 SEQ ID NO: 1929 AAV2/3 variant 4212 WO2018071831 SEQ ID NO: 1930 AAV2/3 variant 4213 WO2018071831 SEQ ID NO: 1931 AAV2/3 variant 4214 WO2018071831 SEQ ID NO: 1932 AAV2/3 variant 4215 WO2018071831 SEQ ID NO: 1933 AAV2/3 variant 4216 WO2018071831 SEQ ID NO: 1934 AAV2/3 variant 4217 WO2018071831 SEQ ID NO: 1935 AAV2/3 variant 4218 WO2018071831 SEQ ID NO: 1936 AAV2/3 variant 4219 WO2018071831 SEQ ID NO: 1937 AAV2/3 variant 4220 WO2018071831 SEQ ID NO: 1938 AAV2/3 variant 4221 WO2018071831 SEQ ID NO: 1939 AAV2/3 variant 4222 WO2018071831 SEQ ID NO: 1940 AAV2/3 variant 4223 WO2018071831 SEQ ID NO: 1941 AAV2/3 variant 4224 WO2018071831 SEQ ID NO: 1942 AAV2/3 variant 4225 WO2018071831 SEQ ID NO: 1943 AAV2/3 variant 4226 WO2018071831 SEQ ID NO: 1944 AAV2/3 variant 4227 WO2018071831 SEQ ID NO: 1945 AAV2/3 variant 4228 WO2018071831 SEQ ID NO: 1946 AAV2/3 variant 4229 WO2018071831 SEQ ID NO: 1947 AAV2/3 variant 4230 WO2018071831 SEQ ID NO: 1948 AAV2/3 variant 4231 WO2018071831 SEQ ID NO: 1949 AAV2/3 variant 4232 WO2018071831 SEQ ID NO: 1950 AAV2/3 variant 4233 WO2018071831 SEQ ID NO: 1951 AAV2/3 variant 4234 WO2018071831 SEQ ID NO: 1952 AAV2/3 variant 4235 WO2018071831 SEQ ID NO: 1953 AAV2/3 variant 4236 WO2018071831 SEQ ID NO: 1954 AAV2/3 variant 4237 WO2018071831 SEQ ID NO: 1955 AAV2/3 variant 4238 WO2018071831 SEQ ID NO: 1956 AAV2/3 variant 4239 WO2018071831 SEQ ID NO: 1957 AAV2/3 variant 4240 WO2018071831 SEQ ID NO: 1958 AAV2/3 variant 4241 WO2018071831 SEQ ID NO: 1959 AAV2/3 variant 4242 WO2018071831 SEQ ID NO: 1960 AAV2/3 variant 4243 WO2018071831 SEQ ID NO: 1961 AAV2/3 variant 4244 WO2018071831 SEQ ID NO: 1962 AAV2/3 variant 4245 WO2018071831 SEQ ID NO: 1963 AAV2/3 variant 4246 WO2018071831 SEQ ID NO: 1964 AAV2/3 variant 4247 WO2018071831 SEQ ID NO: 1965 AAV2/3 variant 4248 WO2018071831 SEQ ID NO: 1966 AAV2/3 variant 4249 WO2018071831 SEQ ID NO: 1967 AAV2/3 variant 4250 WO2018071831 SEQ ID NO: 1968 AAV2/3 variant 4251 WO2018071831 SEQ ID NO: 1969 AAV2/3 variant 4252 WO2018071831 SEQ ID NO: 1970 AAV2/3 variant 4253 WO2018071831 SEQ ID NO: 1971 AAV2/3 variant 4254 WO2018071831 SEQ ID NO: 1972 AAV2/3 variant 4255 WO2018071831 SEQ ID NO: 1973 AAV2/3 variant 4256 WO2018071831 SEQ ID NO: 1974 AAV2/3 variant 4257 WO2018071831 SEQ ID NO: 1975 AAV2/3 variant 4258 WO2018071831 SEQ ID NO: 1976 AAV2/3 variant 4259 WO2018071831 SEQ ID NO: 1977 AAV2/3 variant 4260 WO2018071831 SEQ ID NO: 1978 AAV2/3 variant 4261 WO2018071831 SEQ ID NO: 1979 AAV2/3 variant 4262 WO2018071831 SEQ ID NO: 1980 AAV2/3 variant 4263 WO2018071831 SEQ ID NO: 1981 AAV2/3 variant 4264 WO2018071831 SEQ ID NO: 1982 AAV2/3 variant 4265 WO2018071831 SEQ ID NO: 1983 AAV2/3 variant 4266 WO2018071831 SEQ ID NO: 1984 AAV2/3 variant 4267 WO2018071831 SEQ ID NO: 1985 AAV2/3 variant 4268 WO2018071831 SEQ ID NO: 1986 AAV2/3 variant 4269 WO2018071831 SEQ ID NO: 1987 AAV2/3 variant 4270 WO2018071831 SEQ ID NO: 1988 AAV2 variant 4271 WO2018071831 SEQ ID NO: 1989 AAV2 variant 4272 WO2018071831 SEQ ID NO: 1990 AAV2 variant 4273 WO2018071831 SEQ ID NO: 1991 AAV2 variant 4274 WO2018071831 SEQ ID NO: 1992 AAV2 variant 4275 WO2018071831 SEQ ID NO: 1993 AAV2 variant 4276 WO2018071831 SEQ ID NO: 1994 AAV2 variant 4277 WO2018071831 SEQ ID NO: 1995 AAV2 variant 4278 WO2018071831 SEQ ID NO: 1996 AAV2 variant 4279 WO2018071831 SEQ ID NO: 1997 AAV2 variant 4280 WO2018071831 SEQ ID NO: 1998 AAV2 variant 4281 WO2018071831 SEQ ID NO: 1999 AAV2 variant 4282 WO2018071831 SEQ ID NO: 2000 AAV2 variant 4283 WO2018071831 SEQ ID NO: 2001 AAV2 variant 4284 WO2018071831 SEQ ID NO: 2002 AAV2 variant 4285 WO2018071831 SEQ ID NO: 2003 AAV2 variant 4286 WO2018071831 SEQ ID NO: 2004 AAV2 variant 4287 WO2018071831 SEQ ID NO: 2005 AAV2 variant 4288 WO2018071831 SEQ ID NO: 2006 AAV2 variant 4289 WO2018071831 SEQ ID NO: 2007 AAV2 variant 4290 WO2018071831 SEQ ID NO: 2008 AAV2 variant 4291 WO2018071831 SEQ ID NO: 2009 AAV2 variant 4292 WO2018071831 SEQ ID NO: 2010 AAV2 variant 4293 WO2018071831 SEQ ID NO: 2011 AAV2 variant 4294 WO2018071831 SEQ ID NO: 2012 AAV2 variant 4295 WO2018071831 SEQ ID NO: 2013 AAV2 variant 4296 WO2018071831 SEQ ID NO: 2014 AAV2 variant 4297 WO2018071831 SEQ ID NO: 2015 AAV2 variant 4298 WO2018071831 SEQ ID NO: 2016 AAV2 variant 4299 WO2018071831 SEQ ID NO: 2017 AAV2 variant 4300 WO2018071831 SEQ ID NO: 2018 AAV2 variant 4301 WO2018071831 SEQ ID NO: 2019 AAV2 variant 4302 WO2018071831 SEQ ID NO: 2020 AAV2 variant 4303 WO2018071831 SEQ ID NO: 2021 AAV2 variant 4304 WO2018071831 SEQ ID NO: 2022 AAV2 variant 4305 WO2018071831 SEQ ID NO: 2023 AAV2 variant 4306 WO2018071831 SEQ ID NO: 2024 AAV2 variant 4307 WO2018071831 SEQ ID NO: 2025 AAV2 variant 4308 WO2018071831 SEQ ID NO: 2026 AAV2 variant 4309 WO2018071831 SEQ ID NO: 2027 AAV2 variant 4310 WO2018071831 SEQ ID NO: 2028 AAV2 variant 4311 WO2018071831 SEQ ID NO: 2029 AAV2 variant 4312 WO2018071831 SEQ ID NO: 2030 AAV2 variant 4313 WO2018071831 SEQ ID NO: 2031 AAV2 variant 4314 WO2018071831 SEQ ID NO: 2032 AAV2 variant 4315 WO2018071831 SEQ ID NO: 2033 AAV2 variant 4316 WO2018071831 SEQ ID NO: 2034 AAV2 variant 4317 WO2018071831 SEQ ID NO: 2035 AAV2 variant 4318 WO2018071831 SEQ ID NO: 2036 AAV2 variant 4319 WO2018071831 SEQ ID NO: 2037 AAV2 variant 4320 WO2018071831 SEQ ID NO: 2038 AAV2 variant 4321 WO2018071831 SEQ ID NO: 2039 AAV2 variant 4322 WO2018071831 SEQ ID NO: 2040 AAV2 variant 4323 WO2018071831 SEQ ID NO: 2041 AAV2 variant 4324 WO2018071831 SEQ ID NO: 2042 AAV2 variant 4325 WO2018071831 SEQ ID NO: 2043 AAV2 variant 4326 WO2018071831 SEQ ID NO: 2044 AAV2 variant 4327 WO2018071831 SEQ ID NO: 2045 AAV2 variant 4328 WO2018071831 SEQ ID NO: 2046 AAV2 variant 4329 WO2018071831 SEQ ID NO: 2047 AAV2 variant 4330 WO2018071831 SEQ ID NO: 2048 AAV2 variant 4331 WO2018071831 SEQ ID NO: 2049 AAV2 variant 4332 WO2018071831 SEQ ID NO: 2050 AAV2 variant 4333 WO2018071831 SEQ ID NO: 2051 AAV2 variant 4334 WO2018071831 SEQ ID NO: 2052 AAV2 variant 4335 WO2018071831 SEQ ID NO: 2053 AAV2 variant 4336 WO2018071831 SEQ ID NO: 2054 AAV2 variant 4337 WO2018071831 SEQ ID NO: 2055 AAV2 variant 4338 WO2018071831 SEQ ID NO: 2056 AAV2 variant 4339 WO2018071831 SEQ ID NO: 2057 AAV2 variant 4340 WO2018071831 SEQ ID NO: 2058 AAV2 variant 4341 WO2018071831 SEQ ID NO: 2059 AAV2 variant 4342 WO2018071831 SEQ ID NO: 2060 AAV2 variant 4343 WO2018071831 SEQ ID NO: 2061 AAV2 variant 4344 WO2018071831 SEQ ID NO: 2062 AAV2 variant 4345 WO2018071831 SEQ ID NO: 2063 AAV2 variant 4346 WO2018071831 SEQ ID NO: 2064 AAV2 variant 4347 WO2018071831 SEQ ID NO: 2065 AAV2 variant 4348 WO2018071831 SEQ ID NO: 2066 AAV2 variant 4349 WO2018071831 SEQ ID NO: 2067 AAV2 variant 4350 WO2018071831 SEQ ID NO: 2068 AAV2 variant 4351 WO2018071831 SEQ ID NO: 2069 AAV2 variant 4352 WO2018071831 SEQ ID NO: 2070 AAV2 variant 4353 WO2018071831 SEQ ID NO: 2071 AAV2 variant 4354 WO2018071831 SEQ ID NO: 2072 AAV2 variant 4355 WO2018071831 SEQ ID NO: 2073 AAV2 variant 4356 WO2018071831 SEQ ID NO: 2074 AAV2 variant 4357 WO2018071831 SEQ ID NO: 2075 AAV2 variant 4358 WO2018071831 SEQ ID NO: 2076 AAV2 variant 4359 WO2018071831 SEQ ID NO: 2077 AAV2/3 variant 4360 WO2018071831 SEQ ID NO: 2078 AAV2/3 variant 4361 WO2018071831 SEQ ID NO: 2079 AAV2/3 variant 4362 WO2018071831 SEQ ID NO: 2080 AAV2/3 variant 4363 WO2018071831 SEQ ID NO: 2081 AAV2/3 variant 4364 WO2018071831 SEQ ID NO: 2082 AAV2/3 variant 4365 WO2018071831 SEQ ID NO: 2083 AAV2/3 variant 4366 WO2018071831 SEQ ID NO: 2084 AAV2/3 variant 4367 WO2018071831 SEQ ID NO: 2085 AAV2/3 variant 4368 WO2018071831 SEQ ID NO: 2086 AAV2/3 variant 4369 WO2018071831 SEQ ID NO: 2087 AAV2/3 variant 4370 WO2018071831 SEQ ID NO: 2088 AAV2/3 variant 4371 WO2018071831 SEQ ID NO: 2089 AAV2/3 variant 4372 WO2018071831 SEQ ID NO: 2090 AAV2/3 variant 4373 WO2018071831 SEQ ID NO: 2091 AAV2/3 variant 4374 WO2018071831 SEQ ID NO: 2092 AAV2/3 variant 4375 WO2018071831 SEQ ID NO: 2093 AAV2/3 variant 4376 WO2018071831 SEQ ID NO: 2094 AAV2/3 variant 4377 WO2018071831 SEQ ID NO: 2095 AAV2/3 variant 4378 WO2018071831 SEQ ID NO: 2096 AAV2/3 variant 4379 WO2018071831 SEQ ID NO: 2097 AAV2/3 variant 4380 WO2018071831 SEQ ID NO: 2098 AAV2/3 variant 4381 WO2018071831 SEQ ID NO: 2099 AAV2/3 variant 4382 WO2018071831 SEQ ID NO: 2100 AAV2/3 variant 4383 WO2018071831 SEQ ID NO: 2101 AAV2/3 variant 4384 WO2018071831 SEQ ID NO: 2102 AAV2/3 variant 4385 WO2018071831 SEQ ID NO: 2103 AAV2/3 variant 4386 WO2018071831 SEQ ID NO: 2104 AAV2/3 variant 4387 WO2018071831 SEQ ID NO: 2105 AAV2/3 variant 4388 WO2018071831 SEQ ID NO: 2106 AAV2/3 variant 4389 WO2018071831 SEQ ID NO: 2107 AAV2/3 variant 4390 WO2018071831 SEQ ID NO: 2108 AAV2/3 variant 4391 WO2018071831 SEQ ID NO: 2109 AAV2/3 variant 4392 WO2018071831 SEQ ID NO: 2110 AAV2/3 variant 4393 WO2018071831 SEQ ID NO: 2111 AAV2/3 variant 4394 WO2018071831 SEQ ID NO: 2112 AAV2/3 variant 4395 WO2018071831 SEQ ID NO: 2113 AAV2/3 variant 4396 WO2018071831 SEQ ID NO: 2114 AAV2/3 variant 4397 WO2018071831 SEQ ID NO: 2115 AAV2/3 variant 4398 WO2018071831 SEQ ID NO: 2116 AAV2/3 variant 4399 WO2018071831 SEQ ID NO: 2117 AAV2/3 variant 4400 WO2018071831 SEQ ID NO: 2118 AAV2/3 variant 4401 WO2018071831 SEQ ID NO: 2119 AAV2/3 variant 4402 WO2018071831 SEQ ID NO: 2120 AAV2/3 variant 4403 WO2018071831 SEQ ID NO: 2121 AAV2/3 variant 4404 WO2018071831 SEQ ID NO: 2122 AAV2/3 variant 4405 WO2018071831 SEQ ID NO: 2123 AAV2/3 variant 4406 WO2018071831 SEQ ID NO: 2124 AAV2/3 variant 4407 WO2018071831 SEQ ID NO: 2125 AAV2/3 variant 4408 WO2018071831 SEQ ID NO: 2126 AAV2/3 variant 4409 WO2018071831 SEQ ID NO: 2127 AAV2/3 variant 4410 WO2018071831 SEQ ID NO: 2128 AAV2/3 variant 4411 WO2018071831 SEQ ID NO: 2129 AAV2/3 variant 4412 WO2018071831 SEQ ID NO: 2130 AAV2/3 variant 4413 WO2018071831 SEQ ID NO: 2131 AAV2/3 variant 4414 WO2018071831 SEQ ID NO: 2132 AAV2/3 variant 4415 WO2018071831 SEQ ID NO: 2133 AAV2/3 variant 4416 WO2018071831 SEQ ID NO: 2134 AAV2/3 variant 4417 WO2018071831 SEQ ID NO: 2135 AAV2/3 variant 4418 WO2018071831 SEQ ID NO: 2136 AAV2/3 variant 4419 WO2018071831 SEQ ID NO: 2137 AAV2/3 variant 4420 WO2018071831 SEQ ID NO: 2138 AAV2/3 variant 4421 WO2018071831 SEQ ID NO: 2139 AAV2/3 variant 4422 WO2018071831 SEQ ID NO: 2140 AAV2/3 variant 4423 WO2018071831 SEQ ID NO: 2141 AAV2/3 variant 4424 WO2018071831 SEQ ID NO: 2142 AAV2/3 variant 4425 WO2018071831 SEQ ID NO: 2143 AAV2/3 variant 4426 WO2018071831 SEQ ID NO: 2144 AAV2/3 variant 4427 WO2018071831 SEQ ID NO: 2145 AAV2/3 variant 4428 WO2018071831 SEQ ID NO: 2146 AAV2/3 variant 4429 WO2018071831 SEQ ID NO: 2147 AAV2/3 variant 4430 WO2018071831 SEQ ID NO: 2148 AAV2/3 variant 4431 WO2018071831 SEQ ID NO: 2149 AAV2/3 variant 4432 WO2018071831 SEQ ID NO: 2150 AAV2/3 variant 4433 WO2018071831 SEQ ID NO: 2151 AAV2/3 variant 4434 WO2018071831 SEQ ID NO: 2152 AAV2/3 variant 4435 WO2018071831 SEQ ID NO: 2153 AAV2/3 variant 4436 WO2018071831 SEQ ID NO: 2154 AAV2/3 variant 4437 WO2018071831 SEQ ID NO: 2155 AAV2/3 variant 4438 WO2018071831 SEQ ID NO: 2156 AAV2/3 variant 4439 WO2018071831 SEQ ID NO: 2157 AAV2/3 variant 4440 WO2018071831 SEQ ID NO: 2158 AAV2/3 variant 4441 WO2018071831 SEQ ID NO: 2159 AAV2/3 variant 4442 WO2018071831 SEQ ID NO: 2160 AAV2/3 variant 4443 WO2018071831 SEQ ID NO: 2161 AAV2/3 variant 4444 WO2018071831 SEQ ID NO: 2162 AAV2/3 variant 4445 WO2018071831 SEQ ID NO: 2163 AAV2/3 variant 4446 WO2018071831 SEQ ID NO: 2164 AAV2/3 variant 4447 WO2018071831 SEQ ID NO: 2165 AAV2/3 variant 4448 WO2018071831 SEQ ID NO: 2166 AAV2/3 variant 4449 WO2018071831 SEQ ID NO: 2167 AAV2/3 variant 4450 WO2018071831 SEQ ID NO: 2168 AAV2/3 variant 4451 WO2018071831 SEQ ID NO: 2169 AAV2/3 variant 4452 WO2018071831 SEQ ID NO: 2170 AAV2/3 variant 4453 WO2018071831 SEQ ID NO: 2171 AAV2/3 variant 4454 WO2018071831 SEQ ID NO: 2172 AAV2/3 variant 4455 WO2018071831 SEQ ID NO: 2173 AAV2/3 variant 4456 WO2018071831 SEQ ID NO: 2174 AAV2/3 variant 4457 WO2018071831 SEQ ID NO: 2175 AAV2/3 variant 4458 WO2018071831 SEQ ID NO: 2176 AAV2/3 variant 4459 WO2018071831 SEQ ID NO: 2177 AAV2/3 variant 4460 WO2018071831 SEQ ID NO: 2178 AAV2/3 variant 4461 WO2018071831 SEQ ID NO: 2179 AAV2/3 variant 4462 WO2018071831 SEQ ID NO: 2180 AAV2/3 variant 4463 WO2018071831 SEQ ID NO: 2181 AAV2/3 variant 4464 WO2018071831 SEQ ID NO: 2182 AAV2/3 variant 4465 WO2018071831 SEQ ID NO: 2183 AAV2/3 variant 4466 WO2018071831 SEQ ID NO: 2184 AAV2/3 variant 4467 WO2018071831 SEQ ID NO: 2185 AAV2/3 variant 4468 WO2018071831 SEQ ID NO: 2186 AAV2/3 variant 4469 WO2018071831 SEQ ID NO: 2187 AAV2/3 variant 4470 WO2018071831 SEQ ID NO: 2188 AAV2/3 variant 4471 WO2018071831 SEQ ID NO: 2189 AAV2/3 variant 4472 WO2018071831 SEQ ID NO: 2190 AAV2/3 variant 4473 WO2018071831 SEQ ID NO: 2191 AAV2/3 variant 4474 WO2018071831 SEQ ID NO: 2192 AAV2/3 variant 4475 WO2018071831 SEQ ID NO: 2193 AAV2/3 variant 4476 WO2018071831 SEQ ID NO: 2194 AAV2/3 variant 4477 WO2018071831 SEQ ID NO: 2195 AAV2/3 variant 4478 WO2018071831 SEQ ID NO: 2196 AAV2/3 variant 4479 WO2018071831 SEQ ID NO: 2197 AAV2/3 variant 4480 WO2018071831 SEQ ID NO: 2198 AAV2/3 variant 4481 WO2018071831 SEQ ID NO: 2199 AAV2/3 variant 4482 WO2018071831 SEQ ID NO: 2200 AAV2/3 variant 4483 WO2018071831 SEQ ID NO: 2201 AAV2/3 variant 4484 WO2018071831 SEQ ID NO: 2202 AAV2/3 variant 4485 WO2018071831 SEQ ID NO: 2203 AAV2/3 variant 4486 WO2018071831 SEQ ID NO: 2204 AAV2/3 variant 4487 WO2018071831 SEQ ID NO: 2205 AAV2/3 variant 4488 WO2018071831 SEQ ID NO: 2206 AAV2/3 variant 4489 WO2018071831 SEQ ID NO: 2207 AAV2/3 variant 4490 WO2018071831 SEQ ID NO: 2208 AAV2/3 variant 4491 WO2018071831 SEQ ID NO: 2209 AAV2/3 variant 4492 WO2018071831 SEQ ID NO: 2210 AAV2/3 variant 4493 WO2018071831 SEQ ID NO: 2211 AAV2/3 variant 4494 WO2018071831 SEQ ID NO: 2212 AAV2/3 variant 4495 WO2018071831 SEQ ID NO: 2213 AAV2/3 variant 4496 WO2018071831 SEQ ID NO: 2214 AAV2/3 variant 4497 WO2018071831 SEQ ID NO: 2215 AAV2/3 variant 4498 WO2018071831 SEQ ID NO: 2216 AAV2/3 variant 4499 WO2018071831 SEQ ID NO: 2217 AAV2/3 variant 4500 WO2018071831 SEQ ID NO: 2218 AAV2/3 variant 4501 WO2018071831 SEQ ID NO: 2219 AAV2/3 variant 4502 WO2018071831 SEQ ID NO: 2220 AAV2/3 variant 4503 WO2018071831 SEQ ID NO: 2221 AAV2/3 variant 4504 WO2018071831 SEQ ID NO: 2222 AAV2/3 variant 4505 WO2018071831 SEQ ID NO: 2223 AAV2/3 variant 4506 WO2018071831 SEQ ID NO: 2224 AAV2/3 variant 4507 WO2018071831 SEQ ID NO: 2225 AAV2/3 variant 4508 WO2018071831 SEQ ID NO: 2226 AAV2/3 variant 4509 WO2018071831 SEQ ID NO: 2227 AAV2/3 variant 4510 WO2018071831 SEQ ID NO: 2228 AAV2/3 variant 4511 WO2018071831 SEQ ID NO: 2229 AAV2/3 variant 4512 WO2018071831 SEQ ID NO: 2230 AAV2/3 variant 4513 WO2018071831 SEQ ID NO: 2231 AAV2/3 variant 4514 WO2018071831 SEQ ID NO: 2232 AAV2/3 variant 4515 WO2018071831 SEQ ID NO: 2233 AAV2/3 variant 4516 WO2018071831 SEQ ID NO: 2234 AAV2/3 variant 4517 WO2018071831 SEQ ID NO: 2235 AAV2/3 variant 4518 WO2018071831 SEQ ID NO: 2236 AAV2/3 variant 4519 WO2018071831 SEQ ID NO: 2237 AAV2/3 variant 4520 WO2018071831 SEQ ID NO: 2238 AAV2/3 variant 4521 WO2018071831 SEQ ID NO: 2239 AAV2/3 variant 4522 WO2018071831 SEQ ID NO: 2240 AAV2/3 variant 4523 WO2018071831 SEQ ID NO: 2241 AAV2/3 variant 4524 WO2018071831 SEQ ID NO: 2242 AAV2/3 variant 4525 WO2018071831 SEQ ID NO: 2243 AAV2/3 variant 4526 WO2018071831 SEQ ID NO: 2244 AAV2/3 variant 4527 WO2018071831 SEQ ID NO: 2245 AAV2/3 variant 4528 WO2018071831 SEQ ID NO: 2246 AAV2/3 variant 4529 WO2018071831 SEQ ID NO: 2247 AAV2/3 variant 4530 WO2018071831 SEQ ID NO: 2248 AAV2/3 variant 4531 WO2018071831 SEQ ID NO: 2249 AAV2/3 variant 4532 WO2018071831 SEQ ID NO: 2250 AAV2/3 variant 4533 WO2018071831 SEQ ID NO: 2251

In some embodiments, the AAV serotype may be, or may have a sequence as described in International Patent Publication WO2015038958, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV9 (SEQ ID NO: 2 and 11 of WO2015038958 or SEQ ID NO: 137 and 138 respectively herein), PHP.B (SEQ ID NO: 8 and 9 of WO2015038958, herein SEQ ID NO: 5 and 6), G2B-13 (SEQ ID NO: 12 of WO2015038958, herein SEQ ID NO: 7), G2B-26 (SEQ ID NO: 13 of WO2015038958, herein SEQ ID NO: 5), TH1.1-32 (SEQ ID NO: 14 of WO2015038958, herein SEQ ID NO: 8), TH1.1-35 (SEQ ID NO: 15 of WO2015038958, herein SEQ ID NO: 9) or variants thereof. Further, any of the targeting peptides or amino acid inserts described in WO2015038958, may be inserted into any parent AAV serotype, such as, but not limited to, AAV9 (SEQ ID NO: 137 for the DNA sequence and SEQ ID NO: 138 for the amino acid sequence). In some embodiments, the amino acid insert is inserted between amino acids 586-592 of the parent AAV (e.g., AAV9). In another embodiment, the amino acid insert is inserted between amino acids 588-589 of the parent AAV sequence. The amino acid insert may be, but is not limited to, any of the following amino acid sequences, TLAVPFK (SEQ ID NO: 1 of WO2015038958; herein SEQ ID NO: 1262), KFPVALT (SEQ ID NO: 3 of WO2015038958; herein SEQ ID NO: 1263), LAVPFK (SEQ ID NO: 31 of WO2015038958; herein SEQ ID NO: 1264), AVPFK (SEQ ID NO: 32 of WO2015038958; herein SEQ ID NO: 1265), VPFK (SEQ ID NO: 33 of WO2015038958; herein SEQ ID NO: 1266), TLAVPF (SEQ ID NO: 34 of WO2015038958; herein SEQ ID NO: 1267), TLAVP (SEQ ID NO: 35 of WO2015038958; herein SEQ ID NO: 1268), TLAV (SEQ ID NO: 36 of WO2015038958; herein SEQ ID NO: 1269), SVSKPFL (SEQ ID NO: 28 of WO2015038958; herein SEQ ID NO: 1270), FTLTTPK (SEQ ID NO: 29 of WO2015038958; herein SEQ ID NO: 1271), MNATKNV (SEQ ID NO: 30 of WO2015038958; herein SEQ ID NO: 1272), QSSQTPR (SEQ ID NO: 54 of WO2015038958; herein SEQ ID NO: 1273), ILGTGTS (SEQ ID NO: 55 of WO2015038958; herein SEQ ID NO: 1274), TRTNPEA (SEQ ID NO: 56 of WO2015038958; herein SEQ ID NO: 1275), NGGTSSS (SEQ ID NO: 58 of WO2015038958; herein SEQ ID NO: 1276), or YTLSQGW (SEQ ID NO: 60 of WO2015038958; herein SEQ ID NO: 1277). Non-limiting examples of nucleotide sequences that may encode the amino acid inserts include the following, AAGTTTCCTGTGGCGTTGACT (for SEQ ID NO: 3 of WO2015038958; herein SEQ ID NO: 1278), ACTTTGGCGGTGCCTTTTAAG (SEQ ID NO: 24 and 49 of WO2015038958; herein SEQ ID NO: 1279), AGTGTGAGTAAGCCTTTTTTG (SEQ ID NO: 25 of WO2015038958; herein SEQ ID NO: 1280), TTTACGTTGACGACGCCTAAG (SEQ ID NO: 26 of WO2015038958; herein SEQ ID NO: 1281), ATGAATGCTACGAAGAATGTG (SEQ ID NO: 27 of WO2015038958; herein SEQ ID NO: 1282), CAGTCGTCGCAGACGCCTAGG (SEQ ID NO: 48 of WO2015038958; herein SEQ ID NO: 1283), ATTCTGGGGACTGGTACTTCG (SEQ ID NO: 50 and 52 of WO2015038958; herein SEQ ID NO: 1284). ACGCGGACTAATCCTGAGGCT (SEQ ID NO: 51 of WO2015038958; herein SEQ ID NO: 1285). AATGGGGGGACTAGTAGTTCT (SEQ ID NO: 53 of WO2015038958; herein SEQ ID NO: 1286), or TATACTTTGTCGCAGGGTTGG (SEQ ID NO: 59 of WO2015038958; herein SEQ ID NO: 1287).

In some embodiments, the AAV serotype may be, or may have a sequence as described in International Patent Publication WO2017100671, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV9 (SEQ ID NO: 45 of WO2017100671, herein SEQ ID NO: 11). PHP.N (SEQ ID NO: 46 of WO2017100671, herein SEQ ID NO: 4), PHP.S (SEQ ID NO: 47 of WO2017100671, herein SEQ ID NO: 10), or variants thereof. Further, any of the targeting peptides or amino acid inserts described in WO2017100671 may be inserted into any parent AAV serotype, such as, but not limited to, AAV9. In some embodiments, the amino acid insert is inserted between amino acids 586-592 of the parent AAV (e.g., AAV9). In another embodiment, the amino acid insert is inserted between amino acids 588-589 of the parent AAV sequence. The amino acid insert may be, but is not limited to, any of the following amino acid sequences, AQTLAVPFKAQ (SEQ ID NO: 1 of WO2017100671; herein SEQ ID NO: 1288), AQSVSKPFLAQ (SEQ ID NO: 2 of WO2017100671; herein SEQ ID NO: 1289), AQFTLTTPKAQ (SEQ ID NO: 3 in the sequence listing of WO2017100671; herein SEQ ID NO: 1290), DGTLAVPFKAQ (SEQ ID NO: 4 in the sequence listing of WO2017100671; herein SEQ ID NO: 1291), ESTLAVPFKAQ (SEQ ID NO: 5 of WO2017100671; herein SEQ ID NO: 1292), GGTLAVPFKAQ (SEQ ID NO: 6 of WO2017100671; herein SEQ ID NO: 1293), AQTLATPFKAQ (SEQ ID NO: 7 and 33 of WO2017100671; herein SEQ ID NO: 1294), ATTLATPFKAQ (SEQ ID NO: 8 of WO2017100671; herein SEQ ID NO: 1295), DGTLATPFKAQ (SEQ ID NO: 9 of WO2017100671; herein SEQ ID NO: 1296), GGTLATPFKAQ (SEQ ID NO: 10 of WO2017100671; herein SEQ ID NO: 1297), SGSLAVPFKAQ (SEQ ID NO: 11 of WO2017100671; herein SEQ ID NO: 1298), AQTLAQPFKAQ (SEQ ID NO: 12 of WO2017100671; herein SEQ ID NO: 1299), AQTLQQPFKAQ (SEQ ID NO: 13 of WO2017100671; herein SEQ ID NO: 1300), AQTLSNPFKAQ (SEQ ID NO: 14 of WO2017100671; herein SEQ ID NO: 1301), AQTLAVPFSNP (SEQ ID NO: 15 of WO2017100671; herein SEQ ID NO: 1302), QGTLAVPFKAQ (SEQ ID NO: 16 of WO2017100671; herein SEQ ID NO: 1303), NQTLAVPFKAQ (SEQ ID NO: 17 of WO2017100671; herein SEQ ID NO: 1304), EGSLAVPFKAQ (SEQ ID NO: 18 of WO2017100671; herein SEQ ID NO: 1305), SGNLAVPFKAQ (SEQ ID NO: 19 of WO2017100671; herein SEQ ID NO: 1306), EGTLAVPFKAQ (SEQ ID NO: 20 of WO2017100671; herein SEQ ID NO: 1307), DSTLAVPFKAQ (SEQ ID NO: 21 in Table 1 of WO2017100671; herein SEQ ID NO: 1308), AVTLAVPFKAQ (SEQ ID NO: 22 of WO2017100671; herein SEQ ID NO: 1309), AQTLSTPFKAQ (SEQ ID NO: 23 of WO2017100671; herein SEQ ID NO: 1310), AQTLPQPFKAQ (SEQ ID NO: 24 and 32 of WO2017100671; herein SEQ ID NO: 1311), AQTLSQPFKAQ (SEQ ID NO: 25 of WO2017100671; herein SEQ ID NO: 1312), AQTLQLPFKAQ (SEQ ID NO: 26 of WO2017100671; herein SEQ ID NO: 1313), AQTLTMPFKAQ (SEQ ID NO: 27, and 34 of WO2017100671 and SEQ ID NO: 35 in the sequence listing of WO2017100671; herein SEQ ID NO: 1314), AQTLTTPFKAQ (SEQ ID NO: 28 of WO2017100671; herein SEQ ID NO: 1315), AQYTLSQGWAQ (SEQ ID NO: 29 of WO2017100671; herein SEQ ID NO: 1316), AQMNATKNVAQ (SEQ ID NO: 30 of WO2017100671; herein SEQ ID NO: 1317), AQVSGGHHSAQ (SEQ ID NO: 31 of WO2017100671; herein SEQ ID NO: 1318), AQTLTAPFKAQ (SEQ ID NO: 35 in Table 1 of WO2017100671; herein SEQ ID NO: 1319), AQTLSKPFKAQ (SEQ ID NO: 36 of WO2017100671; herein SEQ ID NO: 1320), QAVRTSL (SEQ ID NO: 37 of WO2017100671; herein SEQ ID NO: 1321), YTLSQGW (SEQ ID NO: 38 of WO2017100671; herein SEQ ID NO: 1277), LAKERLS (SEQ ID NO: 39 of WO2017100671; herein SEQ ID NO: 1322), TLAVPFK (SEQ ID NO: 40 in the sequence listing of WO2017100671; herein SEQ ID NO: 1262), SVSKPFL (SEQ ID NO: 41 of WO2017100671; herein SEQ ID NO: 1270), FTLTTPK (SEQ ID NO: 42 of WO2017100671; herein SEQ ID NO: 1271), MNSTKNV (SEQ ID NO: 43 of WO2017100671; herein SEQ ID NO: 1323), VSGGHHS (SEQ ID NO: 44 of WO2017100671, herein SEQ ID NO: 1324), SAQTLAVPFKAQAQ (SEQ ID NO: 48 of WO2017100671; herein SEQ ID NO: 1325), SXXXLAVPFKAQAQ (SEQ ID NO: 49 of WO2017100671 wherein X may be any amino acid; herein SEQ ID NO: 1326), SAQXXXVPFKAQAQ (SEQ ID NO: 50 of WO2017100671 wherein X may be any amino acid; herein SEQ ID NO: 1327), SAQTLXXXFKAQAQ (SEQ ID NO: 51 of WO2017100671 wherein X may be any amino acid; herein SEQ ID NO: 1328), SAQTLAVXXXAQAQ (SEQ ID NO: 52 of WO2017100671 wherein X may be any amino acid; herein SEQ ID NO: 1329). SAQTLAVPFXXXAQ (SEQ ID NO: 53 of WO2017100671 wherein X may be any amino acid; herein SEQ ID NO: 1330), TNHQSAQ (SEQ ID NO: 65 of WO2017100671; herein SEQ ID NO: 1331), AQAQTGW (SEQ ID NO: 66 of WO2017100671; herein SEQ ID NO: 1332), DGTLATPFK (SEQ ID NO: 67 of WO2017100671; herein SEQ ID NO: 1333), DGTLATPFKXX (SEQ ID NO: 68 of WO2017100671 wherein X may be any amino acid; herein SEQ ID NO: 1334), LAVPFKAQ (SEQ ID NO: 80 of WO2017100671; herein SEQ ID NO: 1335), VPFKAQ (SEQ ID NO: 81 of WO2017100671; herein SEQ ID NO: 1336), FKAQ (SEQ ID NO: 82 of WO2017100671; herein SEQ ID NO: 1337), AQTLAV (SEQ ID NO: 83 of WO2017100671; herein SEQ ID NO: 1338), AQTLAVPF (SEQ ID NO: 84 of WO2017100671; herein SEQ ID NO: 1339). QAVR (SEQ ID NO: 85 of WO2017100671; herein SEQ ID NO: 1340), AVRT (SEQ ID NO: 86 of WO2017100671; herein SEQ ID NO: 1341), VRTS (SEQ ID NO: 87 of WO2017100671; herein SEQ ID NO: 1342), RTSL (SEQ ID NO: 88 of WO2017100671; herein SEQ ID NO: 1343), QAVRT (SEQ ID NO: 89 of WO2017100671; herein SEQ ID NO: 1344), AVRTS (SEQ ID NO: 90 of WO2017100671; herein SEQ ID NO: 1345). VRTSL (SEQ ID NO: 91 of WO2017100671; herein SEQ ID NO: 1346), QAVRTS (SEQ ID NO: 92 of WO2017100671; herein SEQ ID NO: 1347), or AVRTSL (SEQ ID NO: 93 of WO2017100671; herein SEQ ID NO: 1348).

Non-limiting examples of nucleotide sequences that may encode the amino acid inserts include the following, GATGGGACTTTGGCGGTGCCTITTAAGGCACAG (SEQ ID NO: 54 of WO2017100671; herein SEQ ID NO: 1349), GATGGGACGTTGGCGGTGCCTITTAAGGCACAG (SEQ ID NO: 55 of WO2017100671; herein SEQ ID NO: 1350), CAGGCGGTTAGGACGTCTTTG (SEQ ID NO: 56 of WO2017100671; herein SEQ ID NO: 1351), CAGGTCTTCACGGACTCAGACTATCAG (SEQ ID NO: 57 and 78 of WO2017100671; herein SEQ ID NO: 1352), CAAGTAAAACCTCTACAAATGTGGTAAAATCG (SEQ ID NO: 58 of WO2017100671; herein SEQ ID NO: 1353), ACTCATCGACCAATACTTGTACTATCTCTCTAGAAC (SEQ ID NO: 59 of WO2017100671; herein SEQ ID NO: 1354), GGAAGTATTCCTTGGTTTTGAACCCA (SEQ ID NO: 60 of WO2017100671; herein SEQ ID NO: 1355), GGTCGCGGTTCTTGTTTGTGGAT (SEQ ID NO: 61 of WO2017100671; herein SEQ ID NO: 1356), CGACCTTGAAGCGCATGAACTCCT (SEQ ID NO: 62 of WO2017100671; herein SEQ ID NO: 1357), GTATTCCTTGGTTTTGAACCCAACCGGTCTGCGCCTGTGCMNNMNNMNNMNNMNNMN NMNNTTGGGCACTCTGGTGGTTTGTC (SEQ ID NO: 63 of WO2017100671 wherein N may be A, C, T. or G; herein SEQ ID NO: 1358), GTATTCCTTGGTTTTGAACCCAACCGGTCTGCGCMNNMNNMNNAAAAGGCACCGCCAA AGTTTG (SEQ ID NO: 69 of WO2017100671 wherein N may be A, C, T, or G; herein SEQ ID NO: 1359), GTATTCCTTGGTTTTGAACCCAACCGGTCTGCGCCTGTGCMNNMNNMNNCACCGCCAA AGTTTGGGCACT (SEQ ID NO: 70 of WO2017100671 wherein N may be A, C, T, or G; herein SEQ ID NO: 1360), GTATTCCTTGGTTTTGAACCCAACCGGTCTGCGCCTGTGCCTTAAAMNNMNNMNNCAAA GTTTGGGCACTCTGGTGG (SEQ ID NO: 71 of WO2017100671 wherein N may be A, C, T, or G; herein SEQ ID NO: 1361), GTATTCCTTGGTTTTGAACCCAACCGGTCTGCGCCTGTGCCTTAAAAGGCACMNNMNNM NNTTGGGCACTCTGGTGGTTTGTG (SEQ ID NO: 72 of WO2017100671 wherein N may be A, C, T, or G; herein SEQ ID NO: 1362), ACTTTGGCGGTGCCTTTTAAG (SEQ ID NO: 74 of WO2017100671; herein SEQ ID NO: 1279), AGTGTGAGTAAGCCTTTTTTG (SEQ ID NO: 75 of WO2017100671; herein SEQ ID NO: 1280), TTTACGTTGACGACGCCTAAG (SEQ ID NO: 76 of WO2017100671; herein SEQ ID NO: 1281), TATACTTTGTCGCAGGGTTGG (SEQ ID NO: 77 of WO2017100671; herein SEQ ID NO: 1287), or CTTGCGAAGGAGCGGCTTTCG (SEQ ID NO: 79 of WO2017100671; herein SEQ ID NO: 1363).

In some embodiments, the AAV serotype may be, or may have a sequence as described in U.S. Pat. No. 9,624,274, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV1 (SEQ ID NO: 181 of U.S. Pat. No. 9,624,274), AAV6 (SEQ ID NO: 182 of U.S. Pat. No. 9,624,274), AAV2 (SEQ ID NO: 183 of U.S. Pat. No. 9,624,274), AAV3b (SEQ ID NO: 184 of U.S. Pat. No. 9,624,274), AAV7 (SEQ ID NO: 185 of U.S. Pat. No. 9,624,274), AAV8 (SEQ ID NO: 186 of U.S. Pat. No. 9,624,274), AAV10 (SEQ ID NO: 187 of U.S. Pat. No. 9,624,274), AAV4 (SEQ ID NO: 188 of U.S. Pat. No. 9,624,274), AAV11 (SEQ ID NO: 189 of U.S. Pat. No. 9,624,274), bAAV (SEQ ID NO: 190 of U.S. Pat. No. 9,624,274), AAV5 (SEQ ID NO: 191 of U.S. Pat. No. 9,624,274), GPV (SEQ ID NO: 192 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 879), B19 (SEQ ID NO: 193 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 880), MVM (SEQ ID NO: 194 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 881), FPV (SEQ ID NO: 195 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 882), CPV (SEQ ID NO: 196 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 883) or variants thereof. Further, any of the structural protein inserts described in U.S. Pat. No. 9,624,274, may be inserted into, but not limited to, 1-453 and 1-587 of any parent AAV serotype, such as, but not limited to, AAV2 (SEQ ID NO: 183 of U.S. Pat. No. 9,624,274). The amino acid insert may be, but is not limited to, any of the following amino acid sequences, VNLTWSRASG (SEQ ID NO: 50 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1364), EFCINHRGYWVCGD (SEQ ID NO:55 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1365), EDGQVMDVDLS (SEQ ID NO: 85 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1366), EKQRNGTLT (SEQ ID NO: 86 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1367), TYQCRVTHPHLPRALMR (SEQ ID NO: 87 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1368), RHSTTQPRKTKGSG (SEQ ID NO: 88 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1369), DSNPRGVSAYLSR (SEQ ID NO: 89 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1370), TITCLWDLAPSK (SEQ ID NO: 90 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1371), KTKGSGFFVF (SEQ ID NO: 91 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1372), THPHLPRALMRS (SEQ ID NO: 92 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1373), GETYQCRVTHPHLPRALMRSTTK (SEQ ID NO: 93 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1374), LPRALMRS (SEQ ID NO: 94 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1375), INHRGYWV (SEQ ID NO: 95 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1376), CDAGSVRTNAPD (SEQ ID NO: 60 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1377), AKAVSNLTESRSESLQS (SEQ ID NO: 96 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1378), SLTGDEFKKVLET (SEQ ID NO: 97 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1379), REAVAYRFEED (SEQ ID NO: 98 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1380), INPEIITLDG (SEQ ID NO: 99 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1381), DISVTGAPVITATYL (SEQ ID NO: 100 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1382), DISVTGAPVITA (SEQ ID NO: 101 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1383), PKTVSNLTESSSESVQS (SEQ ID NO: 102 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1384), SLMGDEFKAVLET (SEQ ID NO: 103 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1385). QHSVAYTFEED (SEQ ID NO: 104 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1386), INPEIITRDG (SEQ ID NO: 105 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1387), DISLTGDPVITASYL (SEQ ID NO: 106 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1388), DISLTGDPVITA (SEQ ID NO: 107 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1389), DQSIDFEIDSA (SEQ ID NO: 108 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1390), KNVSEDLPLPTFSPTLLGDS (SEQ ID NO: 109 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1391), KNVSEDLPLPT (SEQ ID NO: 110 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1392), CDSGRVRTDAPD (SEQ ID NO: 111 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1393), FPEHLLVDFLQSLS (SEQ ID NO: 112 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1394), DAEFRHDSG (SEQ ID NO: 65 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1395), HYAAAQWDFGNTMCQL (SEQ ID NO: 113 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1396), YAAQWDFGNTMCQ (SEQ ID NO: 114 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1397), RSQKEGLHYT (SEQ ID NO: 115 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1398), SSRTPSDKPVAHWANPQAE (SEQ ID NO: 116 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1399), SRTPSDKPVAHWANP (SEQ ID NO: 117 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1400), SSRTPSDKP (SEQ ID NO: 118 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1401), NADGNVDYHMNSVP (SEQ ID NO: 119 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1402), DGNVDYHMNSV (SEQ ID NO: 120 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1403), RSFKEFLQSSLRALRQ (SEQ ID NO: 121 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1404); FKEFLQSSLRA (SEQ ID NO: 122 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1405), or QMWAPQWGPD (SEQ ID NO: 123 of U.S. Pat. No. 9,624,274; herein SEQ ID NO: 1406).

In some embodiments, the AAV serotype may be, or may have a sequence as described in U.S. Pat. No. 9,475,845, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV capsid proteins comprising modification of one or more amino acids at amino acid positions 585 to 590 of the native AAV2 capsid protein. Further the modification may result in, but not be limited to, the amino acid sequence RGNRQA (SEQ ID NO: 3 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1407), SSSTDP (SEQ ID NO: 4 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1408). SSNTAP (SEQ ID NO: 5 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1409), SNSNLP (SEQ ID NO: 6 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1410), SSTTAP (SEQ ID NO: 7 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1411), AANTAA (SEQ ID NO: 8 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1412), QQNTAP (SEQ ID NO: 9 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1413), SAQAQA (SEQ ID NO: 10 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1414), QANTGP (SEQ ID NO: 11 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1415), NATTAP (SEQ ID NO: 12 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1416), SSTAGP (SEQ ID NO: 13 and 20 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1417), QQNTAA (SEQ ID NO: 14 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1418), PSTAGP (SEQ ID NO: 15 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1419), NQNTAP (SEQ ID NO: 16 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1420), QAANAP (SEQ ID NO: 17 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1421), SIVGLP (SEQ ID NO: 18 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1422), AASTAA (SEQ ID NO: 19, and 27 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1423), SQNTTA (SEQ ID NO: 21 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1424), QQDTAP (SEQ ID NO: 22 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1425), QTNTGP (SEQ ID NO: 23 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1426), QTNGAP (SEQ ID NO: 24 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1427), QQNAAP (SEQ ID NO: 25 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1428), or AANTQA (SEQ ID NO: 26 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1429). In some embodiments, the amino acid modification is a substitution at amino acid positions 262 through 265 in the native AAV2 capsid protein or the corresponding position in the capsid protein of another AAV with a targeting sequence. The targeting sequence may be, but is not limited to, any of the amino acid sequences, NGRAHA (SEQ ID NO: 38 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1430), QPEHSST (SEQ ID NO: 39 and 50 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1431). VNTANST (SEQ ID NO: 40 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1432), HGPMQKS (SEQ ID NO: 41 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1433). PHKPPLA (SEQ ID NO: 42 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1434), IKNNEMW (SEQ ID NO: 43 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1435), RNLDTPM (SEQ ID NO: 44 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1436), VDSHRQS (SEQ ID NO: 45 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1437), YDSKTKT (SEQ ID NO: 46 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1438), SQLPHQK (SEQ ID NO: 47 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1439), STMQQNT (SEQ ID NO: 48 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1440), TERYMTQ (SEQ ID NO: 49 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1441), DASLSTS (SEQ ID NO: 51 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1442), DLPNKKT (SEQ ID NO: 52 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1443), DLTAARL (SEQ ID NO: 53 of U.S. Pat. No. 9,475,845; hercin SEQ ID NO: 1444), EPHQFNY (SEQ ID NO: 54 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1445), EPQSNHT (SEQ ID NO: 55 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1446), MSSWPSQ (SEQ ID NO: 56 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1447), NPKHNAT (SEQ ID NO: 57 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1448), PDGMRTT (SEQ ID NO: 58 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1449), PNNNKTT (SEQ ID NO: 59 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1450), QSTTHDS (SEQ ID NO: 60 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1451), TGSKQKQ (SEQ ID NO: 61 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1452), SLKHQAL (SEQ ID NO: 62 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1453), SPIDGEQ (SEQ ID NO: 63 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1454), WIFPWIQL (SEQ ID NO: 64 and 112 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1455), CDCRGDCFC (SEQ ID NO: 65 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1456), CNGRC (SEQ ID NO: 66 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1457), CPRECES (SEQ ID NO: 67 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1458), CTTHWGFTLC (SEQ ID NO: 68 and 123 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1459), CGRRAGGSC (SEQ ID NO: 69 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1460), CKGGRAKDC (SEQ ID NO: 70 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1461), CVPELGHEC (SEQ ID NO: 71 and 115 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1462), CRRETAWAK (SEQ ID NO: 72 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1463), VSWFSHRYSPFAVS (SEQ ID NO: 73 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1464), GYRDGYAGPILYN (SEQ ID NO: 74 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1465). XXXYXXX (SEQ ID NO: 75 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1466), YXNW (SEQ ID NO: 76 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1467), RPLPPLP (SEQ ID NO: 77 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1468), APPLPPR (SEQ ID NO: 78 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1469), DVFYPYPYASGS (SEQ ID NO: 79 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1470), MYWYPY (SEQ ID NO: 80 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1471), DITWDQLWDLMK (SEQ ID NO: 81 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1472), CWDDXWLC (SEQ ID NO: 82 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1473), EWCEYLGGYLRCYA (SEQ ID NO: 83 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1474), YXCXXGPXTWXCXP (SEQ ID NO: 84 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1475), IEGPTLRQWLAARA (SEQ ID NO: 85 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1476), LWXXX (SEQ ID NO: 86 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1477), XFXXYLW (SEQ ID NO: 87 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1478), SSIISHFRWGLCD (SEQ ID NO: 88 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1479), MSRPACPPNDKYE (SEQ ID NO: 89 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1480), CLRSGRGC (SEQ ID NO: 90 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1481), CHWMFSPWC (SEQ ID NO: 91 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1482), WXXF (SEQ ID NO: 92 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1483), CSSRLDAC (SEQ ID NO: 93 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1484), CLPVASC (SEQ ID NO: 94 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1485), CGFECVRQCPERC (SEQ ID NO: 95 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1486), CVALCREACGEGC (SEQ ID NO: 96 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1487), SWCEPGWCR (SEQ ID NO: 97 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1488), YSGKWGW (SEQ ID NO: 98 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1489), GLSGGRS (SEQ ID NO: 99 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1490). LMLPRAD (SEQ ID NO: 100 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1491). CSCFRDVCC (SEQ ID NO: 101 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1492), CRDVVSVIC (SEQ ID NO: 102 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1493), MARSGL (SEQ ID NO: 103 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1494), MARAKE (SEQ ID NO: 104 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1495), MSRTMS (SEQ ID NO: 105 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1496, KCCYSL (SEQ ID NO: 106 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1497), MYWGDSHWLQYWYE (SEQ ID NO: 107 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1498), MQLPLAT (SEQ ID NO: 108 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1499), EWLS (SEQ ID NO: 109 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1500), SNEW (SEQ ID NO: 110 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1501), TNYL (SEQ ID NO: 111 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1502), WDLAWMFRLPVG (SEQ ID NO: 113 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1503), CTVALPGGYVRVC (SEQ ID NO: 114 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1504), CVAYCIEHHCWTC (SEQ ID NO: 116 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1505), CVFAHNYDYLVC (SEQ ID NO: 117 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1506), CVFTSNYAFC (SEQ ID NO: 118 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1507), VHSPNKK (SEQ ID NO: 119 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1508), CRGDGWC (SEQ ID NO: 120 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1509), XRGCDX (SEQ ID NO: 121 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1510). PXXX (SEQ ID NO: 122 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1511). SGKGPRQITAL (SEQ ID NO: 124 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1512), AAAAAAAAAXXXXX (SEQ ID NO: 125 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1513), VYMSPF (SEQ ID NO: 126 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1514), ATWLPPR (SEQ ID NO: 127 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1515), HTMYYHHYQHHL (SEQ ID NO: 128 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1516), SEVGCRAGPLQWLCEKYFG (SEQ ID NO: 129 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1517), CGLLPVGRPDRNVWRWLC (SEQ ID NO: 130 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1518), CKGQCDRFKGLPWEC (SEQ ID NO: 131 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1519), SGRSA (SEQ ID NO: 132 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1520). WGFP (SEQ ID NO: 133 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1521), AEPMPHSLNFSQYLWYT (SEQ ID NO: 134 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1522), WAYXSP (SEQ ID NO: 135 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1523), IELLQAR (SEQ ID NO: 136 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1524), AYTKCSRQWRTCMTTH (SEQ ID NO: 137 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1525), PQNSKIPGPTFLDPH (SEQ ID NO: 138 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1526), SMEPALPDWWWKMFK (SEQ ID NO: 139 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1527), ANTPCGPYTHDCPVKR (SEQ ID NO: 140 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1528), TACHQHVRMVRP (SEQ ID NO: 141 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1529), VPWMEPAYQRFL (SEQ ID NO: 142 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1530), DPRATPGS (SEQ ID NO: 143 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1531), FRPNRAQDYNTN (SEQ ID NO: 144 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1532), CTKNSYLMC (SEQ ID NO: 145 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1533), CXXTXXXGXGC (SEQ ID NO: 146 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1534), CPIEDRPMC (SEQ ID NO: 147 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1535), HEWSYLAPYPWF (SEQ ID NO: 148 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1536), MCPKHPLGC (SEQ ID NO: 149 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1537), RMWPSSTVNLSAGRR (SEQ ID NO: 150 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1538), SAKTAVSQRVWLPSHRGGEP (SEQ ID NO: 151 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1539), KSREHVNNSACPSKRITAAL (SEQ ID NO: 152 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1540), EGFR (SEQ ID NO: 153 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1541), AGLGVR (SEQ ID NO: 154 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1542), GTRQGHTMRLGVSDG (SEQ ID NO: 155 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1543), IAGLATPGWSHWLAL (SEQ ID NO: 156 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1544), SMSIARL (SEQ ID NO: 157 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1545), HTFEPGV (SEQ ID NO: 158 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1546). NTSLKRISNKRIRRK (SEQ ID NO: 159 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1547). LRIKRKRRKRKKTRK (SEQ ID NO: 160 of U.S. Pat. No. 9,475,845; herein SEQ ID NO: 1548), GGG, GFS, LWS, EGG, LLV, LSP, LBS, AGG, GRR, GGH and GTV.

In some embodiments, the AAV serotype may be, or may have a sequence as described in United States Publication No. US 20160369298, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, site-specific mutated capsid protein of AAV2 (SEQ ID NO: 97 of US 20160369298; herein SEQ ID NO: 1549) or variants thereof, wherein the specific site is at least one site selected from sites R447. G453, S578, N587, N587+1, S662 of VP1 or fragment thereof.

Further, any of the mutated sequences described in US 20160369298, may be or may have, but not limited to, any of the following sequences SDSGASN (SEQ ID NO: 1 and SEQ ID NO: 231 of US20160369298; herein SEQ ID NO: 1550), SPSGASN (SEQ ID NO: 2 of US20160369298; herein SEQ ID NO: 1551), SHSGASN (SEQ ID NO: 3 of US20160369298; herein SEQ ID NO: 1552), SRSGASN (SEQ ID NO: 4 of US20160369298; herein SEQ ID NO: 1553), SKSGASN (SEQ ID NO: 5 of US20160369298; herein SEQ ID NO: 1554), SNSGASN (SEQ ID NO: 6 of US20160369298; herein SEQ ID NO: 1555), SGSGASN (SEQ ID NO: 7 of US20160369298; herein SEQ ID NO: 1556), SASGASN (SEQ ID NO: 8, 175, and 221 of US20160369298; herein SEQ ID NO: 1557), SESGTSN (SEQ ID NO: 9 of US20160369298; herein SEQ ID NO: 1558), STTGGSN (SEQ ID NO: 10 of US20160369298; herein SEQ ID NO: 1559), SSAGSTN (SEQ ID NO: 11 of US20160369298; herein SEQ ID NO: 1560), NNDSQA (SEQ ID NO: 12 of US20160369298; herein SEQ ID NO: 1561), NNRNQA (SEQ ID NO: 13 of US20160369298; herein SEQ ID NO: 1562), NNNKQA (SEQ ID NO: 14 of US20160369298; herein SEQ ID NO: 1563). NAKRQA (SEQ ID NO: 15 of US20160369298; herein SEQ ID NO: 1564), NDEHQA (SEQ ID NO: 16 of US20160369298; herein SEQ ID NO: 1565), NTSQKA (SEQ ID NO: 17 of US20160369298; herein SEQ ID NO: 1566), YYLSRTNTPSGTDTQSRLVFSQAGA (SEQ ID NO: 18 of US20160369298; herein SEQ ID NO: 1567), YYLSRTNTDSGTETQSGLDFSQAGA (SEQ ID NO: 19 of US20160369298; herein SEQ ID NO: 1568), YYLSRTNTESGTPTQSALEFSQAGA (SEQ ID NO: 20 of US20160369298; herein SEQ ID NO: 1569), YYLSRTNTHSGTHTQSPLHFSQAGA (SEQ ID NO: 21 of US20160369298; herein SEQ ID NO: 1570), YYLSRTNTSSGTITISHLIFSQAGA (SEQ ID NO: 22 of US20160369298; herein SEQ ID NO: 1571), YYLSRTNTRSGIMTKSSLMFSQAGA (SEQ ID NO: 23 of US20160369298; herein SEQ ID NO: 1572), YYLSRTNTKSGRKTLSNLSFSQAGA (SEQ ID NO: 24 of US20160369298; herein SEQ ID NO: 1573), YYLSRTNDGSGPVTPSKLRFSQRGA (SEQ ID NO: 25 of US20160369298; herein SEQ ID NO: 1574), YYLSRTNAASGHATHSDLKFSQPGA (SEQ ID NO: 26 of US20160369298; herein SEQ ID NO: 1575), YYLSRTNGQAGSLTMSELGFSQVGA (SEQ ID NO: 27 of US20160369298; herein SEQ ID NO: 1576), YYLSRTNSTGGNQTTSQLLFSQLSA (SEQ ID NO: 28 of US20160369298; herein SEQ ID NO: 1577), YFLSRTNNNTGLNTNSTLNFSQGRA (SEQ ID NO: 29 of US20160369298; herein SEQ ID NO: 1578), SKTGADNNNSEYSWTG (SEQ ID NO: 30 of US20160369298; herein SEQ ID NO: 1579), SKTDADNNNSEYSWTG (SEQ ID NO: 31 of US20160369298; herein SEQ ID NO: 1580), SKTEADNNNSEYSWTG (SEQ ID NO: 32 of US20160369298; herein SEQ ID NO: 1581), SKTPADNNNSEYSWTG (SEQ ID NO: 33 of US20160369298; herein SEQ ID NO: 1582), SKTHADNNNSEYSWTG (SEQ ID NO: 34 of US20160369298; herein SEQ ID NO: 1583), SKTQADNNNSEYSWTG (SEQ ID NO: 35 of US20160369298; herein SEQ ID NO: 1584), SKTIADNNNSEYSWTG (SEQ ID NO: 36 of US20160369298; herein SEQ ID NO: 1585), SKTMADNNNSEYSWTG (SEQ ID NO: 37 of US20160369298; herein SEQ ID NO: 1586), SKTRADNNNSEYSWTG (SEQ ID NO: 38 of US20160369298; herein SEQ ID NO: 1587), SKTNADNNNSEYSWTG (SEQ ID NO: 39 of US20160369298; herein SEQ ID NO: 1588). SKTVGRNNNSEYSWTG (SEQ ID NO: 40 of US20160369298; herein SEQ ID NO: 1589), SKTADRNNNSEYSWTG (SEQ ID NO: 41 of US20160369298; herein SEQ ID NO: 1590), SKKLSQNNNSKYSWQG (SEQ ID NO: 42 of US20160369298; herein SEQ ID NO: 1591), SKPTTGNNNSDYSWPG (SEQ ID NO: 43 of US20160369298; herein SEQ ID NO: 1592), STQKNENNNSNYSWPG (SEQ ID NO: 44 of US20160369298; herein SEQ ID NO: 1593), HKDDEGKF (SEQ ID NO: 45 of US20160369298; herein SEQ ID NO: 1594), HKDDNRKF (SEQ ID NO: 46 of US20160369298; herein SEQ ID NO: 1595), HKDDTNKF (SEQ ID NO: 47 of US20160369298; herein SEQ ID NO: 1596), HEDSDKNF (SEQ ID NO: 48 of US20160369298; herein SEQ ID NO: 1597), HRDGADSF (SEQ ID NO: 49 of US20160369298; herein SEQ ID NO: 1598), HGDNKSRF (SEQ ID NO: 50 of US20160369298; herein SEQ ID NO: 1599), KQGSEKTNVDFEEV (SEQ ID NO: 51 of US20160369298; herein SEQ ID NO: 1600), KQGSEKTNVDSEEV (SEQ ID NO: 52 of US20160369298; herein SEQ ID NO: 1601), KQGSEKTNVDVEEV (SEQ ID NO: 53 of US20160369298; herein SEQ ID NO: 1602), KQGSDKTNVDDAGV (SEQ ID NO: 54 of US20160369298; herein SEQ ID NO: 1603), KQGSSKTNVDPREV (SEQ ID NO: 55 of US20160369298; herein SEQ ID NO: 1604), KQGSRKTNVDHKQV (SEQ ID NO: 56 of US20160369298; herein SEQ ID NO: 1605), KQGSKGGNVDTNRV (SEQ ID NO: 57 of US20160369298; herein SEQ ID NO: 1606), KQGSGEANVDNGDV (SEQ ID NO: 58 of US20160369298; herein SEQ ID NO: 1607), KQDAAADNIDYDHV (SEQ ID NO: 59 of US20160369298; herein SEQ ID NO: 1608), KQSGTRSNAAASSV (SEQ ID NO: 60 of US20160369298; herein SEQ ID NO: 1609), KENTNTNDTELTNV (SEQ ID NO: 61 of US20160369298; herein SEQ ID NO: 1610), QRGNNVAATADVNT (SEQ ID NO: 62 of US20160369298; herein SEQ ID NO: 1611). QRGNNEAATADVNT (SEQ ID NO: 63 of US20160369298; herein SEQ ID NO: 1612), QRGNNPAATADVNT (SEQ ID NO: 64 of US20160369298; herein SEQ ID NO: 1613), QRGNNHAATADVNT (SEQ ID NO: 65 of US20160369298; herein SEQ ID NO: 1614), QEENNIAATPGVNT (SEQ ID NO: 66 of US20160369298; herein SEQ ID NO: 1615). QPPNNMAATHEVNT (SEQ ID NO: 67 of US20160369298; herein SEQ ID NO: 1616), QHHNNSAATTIVNT (SEQ ID NO: 68 of US20160369298; herein SEQ ID NO: 1617), QTTNNRAAFNMVET (SEQ ID NO: 69 of US20160369298; herein SEQ ID NO: 1618), QKKNNNAASKKVAT (SEQ ID NO: 70 of US20160369298; herein SEQ ID NO: 1619), QGGNNKAADDAVKT (SEQ ID NO: 71 of US20160369298; herein SEQ ID NO: 1620), QAAKGGAADDAVKT (SEQ ID NO: 72 of US20160369298; herein SEQ ID NO: 1621), QDDRAAAANESVDT (SEQ ID NO: 73 of US20160369298; herein SEQ ID NO: 1622), QQQHDDAAYQRVHT (SEQ ID NO: 74 of US20160369298; herein SEQ ID NO: 1623), QSSSSLAAVSTVQT (SEQ ID NO: 75 of US20160369298; herein SEQ ID NO: 1624), QNNQTTAAIRNVTT (SEQ ID NO: 76 of US20160369298; herein SEQ ID NO: 1625), NYNKKSDNVDFT (SEQ ID NO: 77 of US20160369298; herein SEQ ID NO: 1626), NYNKKSENVDFT (SEQ ID NO: 78 of US20160369298; herein SEQ ID NO: 1627), NYNKKSLNVDFT (SEQ ID NO: 79 of US20160369298; herein SEQ ID NO: 1628), NYNKKSPNVDFT (SEQ ID NO: 80 of US20160369298; herein SEQ ID NO: 1629), NYSKKSHCVDFT (SEQ ID NO: 81 of US20160369298; herein SEQ ID NO: 1630), NYRKTIYVDFT (SEQ ID NO: 82 of US20160369298; herein SEQ ID NO: 1631), NYKEKKDVHFT (SEQ ID NO: 83 of US20160369298; herein SEQ ID NO: 1632), NYGHRAIVQFT (SEQ ID NO: 84 of US20160369298; herein SEQ ID NO: 1633), NYANHQFVVCT (SEQ ID NO: 85 of US20160369298; herein SEQ ID NO: 1634), NYDDDPTGVLLT (SEQ ID NO: 86 of US20160369298; herein SEQ ID NO: 1635), NYDDPTGVLLT (SEQ ID NO: 87 of US20160369298; herein SEQ ID NO: 1636), NFEQQNSVEWT (SEQ ID NO: 88 of US20160369298; herein SEQ ID NO: 1637), SQSGASN (SEQ ID NO: 89 and SEQ ID NO: 241 of US20160369298; herein SEQ ID NO: 1638), NNGSQA (SEQ ID NO: 90 of US20160369298; herein SEQ ID NO: 1639), YYLSRTNTPSGTTTWSRLQFSQAGA (SEQ ID NO: 91 of US20160369298; herein SEQ ID NO: 1640), SKTSADNNNSEYSWTG (SEQ ID NO: 92 of US20160369298; herein SEQ ID NO: 1641), HKDDEEKF (SEQ ID NO: 93, 209, 214, 219, 224, 234, 239, and 244 of US20160369298; herein SEQ ID NO: 1642), KQGSEKTNVDIEEV (SEQ ID NO: 94 of US20160369298; herein SEQ ID NO: 1643), QRGNNQAATADVNT (SEQ ID NO: 95 of US20160369298; herein SEQ ID NO: 1644), NYNKKSVNVDFT (SEQ ID NO: 96 of US20160369298; herein SEQ ID NO: 1645), SQSGASNYNTPSGTTTQSRLQFSTSADNNNSEYSWTGATKYH (SEQ ID NO: 106 of US20160369298; herein SEQ ID NO: 1646), SASGASNFNSEGGSLTQSSLGFSTDGENNNSDFSWTGATKYH (SEQ ID NO: 107 of US20160369298; herein SEQ ID NO: 1647), SQSGASNYNTPSGTTTQSRLQFSTDGENNNSDFSWTGATKYH (SEQ ID NO: 108 of US20160369298; herein SEQ ID NO: 1648), SASGASNYNTPSGTTTQSRLQFSTSADNNNSEFSWPGATTYH (SEQ ID NO: 109 of US20160369298; herein SEQ ID NO: 1649), SQSGASNFNSEGGSLTQSSLGFSTDGENNNSDFSWTGATKYH (SEQ ID NO: 110 of US20160369298; herein SEQ ID NO: 1650), SASGASNYNTPSGSLTQSSLGFSTDGENNNSDFSWTGATKYH (SEQ ID NO: 111 of US20160369298; herein SEQ ID NO: 1651), SQSGASNYNTPSGTTTQSRLQFSTSADNNNSDFSWTGATKYH (SEQ ID NO: 112 of US20160369298; herein SEQ ID NO: 1652), SGAGASNFNSEGGSLTQSSLGFSTDGENNNSDFSWTGATKYH (SEQ ID NO: 113 of US20160369298; herein SEQ ID NO: 1653), SGAGASN (SEQ ID NO: 176 of US20160369298; herein SEQ ID NO: 1654), NSEGGSLTQSSLGFS (SEQ ID NO: 177, 185, 193 and 202 of US20160369298; herein SEQ ID NO: 1655), TDGENNNSDFS (SEQ ID NO: 178 of US20160369298; herein SEQ ID NO: 1656), SEFSWPGATT (SEQ ID NO: 179 of US20160369298; herein SEQ ID NO: 1657), TSADNNNSDFSWT (SEQ ID NO: 180 of US20160369298; herein SEQ ID NO: 1658), SQSGASNY (SEQ ID NO: 181, 187, and 198 of US20160369298; herein SEQ ID NO: 1659), NTPSGTTTQSRLQFS (SEQ ID NO: 182, 188, 191, and 199 of US20160369298; herein SEQ ID NO: 1660), TSADNNNSEYSWTGATKYH (SEQ ID NO: 183 of US20160369298; herein SEQ ID NO: 1661), SASGASNF (SEQ ID NO: 184 of US20160369298; herein SEQ ID NO: 1662), TDGENNNSDFSWTGATKYH (SEQ ID NO: 186, 189, 194, 197, and 203 of US20160369298; herein SEQ ID NO: 1663). SASGASNY (SEQ ID NO: 190 and SEQ ID NO: 195 of US20160369298; herein SEQ ID NO: 1664), TSADNNNSEFSWPGATTYH (SEQ ID NO: 192 of US20160369298; herein SEQ ID NO: 1665), NTPSGSLTQSSLGFS (SEQ ID NO: 196 of US20160369298; herein SEQ ID NO: 1666), TSADNNNSDFSWTGATKYH (SEQ ID NO: 200 of US20160369298; herein SEQ ID NO: 1667), SGAGASNF (SEQ ID NO: 201 of US20160369298; herein SEQ ID NO: 1668), CTCCAGVVSVVSMRSRVCVNSGCAGCTDHCVVSRNSGTCVMSACACAA (SEQ ID NO: 204 of US20160369298; herein SEQ ID NO: 1669), CTCCAGAGAGGCAACAGACAAGCAGCTACCGCAGATGTCAACACACAA (SEQ ID NO: 205 of US20160369298; herein SEQ ID NO: 1670), SAAGASN (SEQ ID NO: 206 of US20160369298; herein SEQ ID NO: 1671), YFLSRTNTESGSTTQSTLRFSQAG (SEQ ID NO: 207 of US20160369298; herein SEQ ID NO: 1672), SKTSADNNNSDFS (SEQ ID NO: 208, 228, and 253 of US20160369298; herein SEQ ID NO: 1673), KQGSEKTDVDIDKV (SEQ ID NO: 210 of US20160369298; herein SEQ ID NO: 1674). STAGASN (SEQ ID NO: 211 of US20160369298; herein SEQ ID NO: 1675), YFLSRTNTTSGIETQSTLRFSQAG (SEQ ID NO: 212 and SEQ ID NO: 247 of US20160369298; herein SEQ ID NO: 1676), SKTDGENNNSDFS (SEQ ID NO: 213 and SEQ ID NO: 248 of US20160369298; herein SEQ ID NO: 1677), KQGAAADDVEIDGV (SEQ ID NO: 215 and SEQ ID NO: 250 of US20160369298; herein SEQ ID NO: 1678), SEAGASN (SEQ ID NO: 216 of US20160369298; herein SEQ ID NO: 1679), YYLSRTNTPSGTTTQSRLQFSQAG (SEQ ID NO: 217, 232 and 242 of US20160369298; herein SEQ ID NO: 1680), SKTSADNNNSEYS (SEQ ID NO: 218, 233, 238, and 243 of US20160369298; herein SEQ ID NO: 1681), KQGSEKTNVDIEKV (SEQ ID NO: 220, 225 and 245 of US20160369298; herein SEQ ID NO: 1682), YFLSRTNDASGSDTKSTLLFSQAG (SEQ ID NO: 222 of US20160369298; herein SEQ ID NO: 1683), STTPSENNNSEYS (SEQ ID NO: 223 of US20160369298; herein SEQ ID NO: 1684), SAAGATN (SEQ ID NO: 226 and SEQ ID NO: 251 of US20160369298; herein SEQ ID NO: 1685), YFLSRTNGEAGSATLSELRFSQAG (SEQ ID NO: 227 of US20160369298; herein SEQ ID NO: 1686), HGDDADRF (SEQ ID NO: 229 and SEQ ID NO: 254 of US20160369298; herein SEQ ID NO: 1687), KQGAEKSDVEVDRV (SEQ ID NO: 230 and SEQ ID NO: 255 of US20160369298; herein SEQ ID NO: 1688), KQDSGGDNIDIDQV (SEQ ID NO: 235 of US20160369298; herein SEQ ID NO: 1689), SDAGASN (SEQ ID NO: 236 of US20160369298; herein SEQ ID NO: 1690), YFLSRTNTEGGHDTQSTLRFSQAG (SEQ ID NO: 237 of US20160369298; herein SEQ ID NO: 1691), KEDGGGSDVAIDEV (SEQ ID NO: 240 of US20160369298; herein SEQ ID NO: 1692), SNAGASN (SEQ ID NO: 246 of US20160369298; herein SEQ ID NO: 1693), and YFLSRTNGEAGSATLSELRFSQPG (SEQ ID NO: 252 of US20160369298; herein SEQ ID NO: 1694). Non-limiting examples of nucleotide sequences that may encode the amino acid mutated sites include the following, AGCVVMDCAGGARSCASCAAC (SEQ ID NO: 97 of US20160369298; herein SEQ ID NO: 1695), AACRACRRSMRSMAGGCA (SEQ ID NO: 98 of US20160369298; herein SEQ ID NO: 1696), CACRRGGACRRCRMSRRSARSTTT (SEQ ID NO: 99 of US20160369298; herein SEQ ID NO: 1697), TATTTCTTGAGCAGAACAAACRVCVVSRSCGGAMNCVHSACGMHSTCAVVSCTTVDSTT TTCTCAGSBCRGSGCG (SEQ ID NO: 100 of US20160369298; herein SEQ ID NO: 1698), TCAAMAMMAVNSRVCSRSAACAACAACAGTRASTTCTCGTGGMMAGGA (SEQ ID NO: 101 of US20160369298; herein SEQ ID NO: 1699), AAGSAARRCRSCRVSRVARVCRATRYCGMSNHCRVMVRSGTC (SEQ ID NO: 102 of US20160369298; herein SEQ ID NO: 1700), CAGVVSVVSMRSRVCVNSGCAGCTDHCVVSRNSGTCVMSACA (SEQ ID NO: 103 of US20160369298; herein SEQ ID NO: 1701), AACTWCRVSVASMVSVHSDDTGTGSWSTKSACT (SEQ ID NO: 104 of US20160369298; herein SEQ ID NO: 1702). TTGTTGAACATCACCACGTGACGCACGTTC (SEQ ID NO: 256 of US20160369298; herein SEQ ID NO: 1703), TCCCCGTGGTTCTACTACATAATGTGGCCG (SEQ ID NO: 257 of US20160369298; herein SEQ ID NO: 1704), TTCCACACTCCGTTTTGGATAATGTTGAAC (SEQ ID NO: 258 of US20160369298; herein SEQ ID NO: 1705), AGGGACATCCCCAGCTCCATGCTGTGGTCG (SEQ ID NO: 259 of US20160369298; herein SEQ ID NO: 1706), AGGGACAACCCCTCCGACTCGCCCTAATCC (SEQ ID NO: 260 of US20160369298; herein SEQ ID NO: 1707), TCCTAGTAGAAGACACCCTCTCACTGCCCG (SEQ ID NO: 261 of US20160369298; herein SEQ ID NO: 1708), AGTACCATGTACACCCACTCTCCCAGTGCC (SEQ ID NO: 262 of US20160369298; herein SEQ ID NO: 1709), ATATGGACGTTCATGCTGATCACCATACCG (SEQ ID NO: 263 of US20160369298; herein SEQ ID NO: 1710), AGCAGGAGCTCCTTGGCCTCAGCGTGCGAG (SEQ ID NO: 264 of US20160369298; herein SEQ ID NO: 1711), ACAAGCAGCTTCACTATGACAACCACTGAC (SEQ ID NO: 265 of US20160369298; herein SEQ ID NO: 1712), CAGCCTAGGAACTGGCTTCCTGGACCCTGTTACCGCCAGCAGAGAGTCTCAAMAMMAV NSRVCSRSAACAACAACAGTRASTTCTCCTGGMMAGGAGCTACCAAGTACCACCTCAAT GGCAGAGACTCTCTGGTGAATCCCGGACCAGCTATGGCAAGCCACRRGGACRRCRMSRR SARSTTTTTTCCTCAGAGCGGGGTTCTCATCTTTGGGAAGSAARRCRSCRVSRVARVCRAT RYCGMSNHCRVMVRSGTCATGATTACAGACGAAGAGGAGATCTGGAC (SEQ ID NO: 266 of US20160369298; herein SEQ ID NO: 1713), TGGGACAATGGCGGTCGTCTCTCAGAGTTKTKKT (SEQ ID NO: 267 of US20160369298; herein SEQ ID NO: 1714), AGAGGACCKKTCCTCGATGGTTCATGGTGGAGTTA (SEQ ID NO: 268 of US20160369298; herein SEQ ID NO: 1715), CCACTTAGGGCCTGGTCGATACCGTTCGGTG (SEQ ID NO: 269 of US20160369298; herein SEQ ID NO: 1716), and TCTCGCCCCAAGAGTAGAAACCCTTCSTTYYG (SEQ ID NO: 270 of US20160369298; herein SEQ ID NO: 1717).

In some embodiments, the AAV serotype may comprise an ocular cell targeting peptide as described in International Patent Publication WO2016134375, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to SEQ ID NO: 9, and SEQ ID NO:10 of WO2016134375. Further, any of the ocular cell targeting peptides or amino acids described in WO2016134375, may be inserted into any parent AAV serotype, such as, but not limited to, AAV2 (SEQ ID NO:8 of WO2016134375; herein SEQ ID NO: 1718), or AAV9 (SEQ ID NO: 11 of WO2016134375; herein SEQ ID NO: 1719). In some embodiments, modifications, such as insertions are made in AAV2 proteins at P34-A35, T138-A139, A139-P140, G453-T454, N587-R588, and/or R588-Q589. In certain embodiments, insertions are made at D384, G385, 1560, T561, N562, E563, E564, E565, N704, and/or Y705 of AAV9. The ocular cell targeting peptide may be, but is not limited to, any of the following amino acid sequences, GSTPPPM (SEQ ID NO: 1 of WO2016134375; herein SEQ ID NO: 1720), or GETRAPL (SEQ ID NO: 4 of WO2016134375; herein SEQ ID NO: 1721).

In some embodiments, the AAV serotype may be modified as described in the United States Publication US 20170145405 the contents of which are herein incorporated by reference in their entirety. AAV serotypes may include, modified AAV2 (e.g., modifications at Y444F. Y500F. Y730F and/or S662V), modified AAV3 (e.g., modifications at Y705F, Y731F and/or T492V), and modified AAV6 (e.g., modifications at S663V and/or T492V).

In some embodiments, the AAV serotype may be modified as described in the International Publication WO2017083722 the contents of which are herein incorporated by reference in their entirety. AAV serotypes may include, AAV1 (Y705+731F+T492V), AAV2 (Y444+500+730F+T491V), AAV3 (Y705+731F), AAV5, AAV 5(Y436+693+719F), AAV6 (VP3 variant Y705F/Y731F/T492V), AAV8 (Y733F), AAV9, AAV9 (VP3 variant Y731F), and AAV10 (Y733F).

In some embodiments, the AAV serotype may comprise, as described in International Patent Publication WO2017015102, the contents of which are herein incorporated by reference in their entirety, an engineered epitope comprising the amino acids SPAKFA (SEQ ID NO: 24 of WO2017015102; herein SEQ ID NO: 1722) or NKDKLN (SEQ ID NO:2 of WO2017015102; herein SEQ ID NO: 1723). The epitope may be inserted in the region of amino acids 665 to 670 based on the numbering of the VP1 capsid of AAV8 (SEQ ID NO: 3 of WO2017015102) and/or residues 664 to 668 of AAV3B (SEQ ID NO: 3).

In some embodiments, the AAV serotype may be, or may have a sequence as described in International Patent Publication WO2017058892, the contents of which are herein incorporated by reference in their entirety, such as, but not limited to, AAV variants with capsid proteins that may comprise a substitution at one or more (e.g., 2, 3, 4, 5, 6, or 7) of amino acid residues 262-268, 370-379,451-459, 472-473,493-500, 528-534, 547-552, 588-597, 709-710, 716-722 of AAV1, in any combination, or the equivalent amino acid residues in AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAVrh8, AAVrh10, AAVrh32.33, bovine AAV or avian AAV. The amino acid substitution may be, but is not limited to, any of the amino acid sequences described in WO2017058892. In some embodiments, the AAV may comprise an amino acid substitution at residues 256L, 258K, 259Q, 261S, 263A, 264S, 265T, 266G, 272H, 385S, 386Q, S472R, V473D, N500E 547S, 709A, 710N, 716D, 717N, 718N, 720L, A456T, Q457T, N458Q, K459S, T492S, K493A, S586R, S587G, S588N, T589R and/or 722T of AAV1 (SEQ ID NO: 1 of WO2017058892) in any combination, 244N, 246Q, 248R, 249E, 250I, 251K, 252S, 253G, 254S, 255V, 256D, 263Y, 377E, 378N, 453L, 456R, 532Q, 533P, 535N, 536P, 537G, 538T, 539T, 540A, 541T, 542Y, 543L, 546N, 653V, 654P, 656S, 697Q, 698F, 704D, 7055, 706T, 707G, 708E, 709Y and/or 710R of AAV5 (SEQ ID NO:5 of WO2017058892) in any combination, 248R, 316V, 317Q, 318D, 319S, 443N, 530N, 531S, 532Q 533P, 534A, 535N, 540A, 541 T, 542Y, 543L, 545G, 546N, 697Q, 704D, 706T, 708E, 709Y and/or 710R of AAV5 (SEQ ID NO: 5 of WO2017058892) in any combination, 264S, 266G, 269N, 272H, 457Q, 588S and/or 5891 of AAV6 (SEQ ID NO:6 WO2017058892) in any combination, 457T, 459N, 496G, 499N, 500N, 589Q, 590N and/or 592A of AAV8 (SEQ ID NO: 8 WO2017058892) in any combination, 4511, 452N, 453G, 454S, 455G, 456Q, 457N and/or 458Q of AAV9 (SEQ ID NO: 9 WO2017058892) in any combination.

In some embodiments, the AAV may include a sequence of amino acids at positions 155, 156 and 157 of VP1 or at positions 17, 18, 19 and 20 of VP2, as described in International Publication No. WO 2017066764, the contents of which are herein incorporated by reference in their entirety. The sequences of amino acid may be, but not limited to, N-S-S, S-X-S, S-S-Y, N-X-S, N-S-Y, S-X-Y and N-X-Y, where N, X and Y are, but not limited to, independently non-serine, or non-threonine amino acids, wherein the AAV may be, but not limited to AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11 and AAV12. In some embodiments, the AAV may include a deletion of at least one amino acid at positions 156, 157 or 158 of VP1 or at positions 19, 20 or 21 of VP2, wherein the AAV may be, but not limited to AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11 and AAV12.

In some embodiments, the AAV may be a serotype generated by Cre-recombination-based AAV targeted evolution (CREATE) as described by Deverman et al., (Nature Biotechnology 34(2):204-209 (2016)), the contents of which are herein incorporated by reference in their entirety. In some embodiments, AAV serotypes generated in this manner have improved CNS transduction and/or neuronal and astrocytic tropism, as compared to other AAV serotypes. As non-limiting examples, the AAV serotype may include a peptide such as, but not limited to, PHP.B, PHP.B2, PHP.B3, PHP.A, PHP.S, G2A12, G2A15, G2A3, G2B4, and G2B5. In some embodiments, these AAV serotypes may be AAV9 (SEQ ID NO: 11 or 138) derivatives with a 7-amino acid insert between amino acids 588-589. Non-limiting examples of these 7-amino acid inserts include TLAVPFK (PHP.B; SEQ ID NO: 1262), SVSKPFL (PHP.B2; SEQ ID NO: 1270), FTLTTPK (PHP.B3; SEQ ID NO: 1271), YTLSQGW (PHP.A; SEQ ID NO: 1277), QAVRTSL (PHP.S; SEQ ID NO: 1321), LAKERLS (G2A3; SEQ ID NO: 1322), MNSTKNV (G2B4; SEQ ID NO: 1323), and/or VSGGHHS (G2B5; SEQ ID NO: 1324).

In some embodiments, the AAV serotype may be as described in Jackson et al (Frontiers in Molecular Neuroscience 9:154 (2016)), the contents of which are herein incorporated by reference in their entirety. In some embodiments, the AAV serotype is PHP.B or AAV9. In some embodiments, the AAV serotype is paired with a synapsin promoter to enhance neuronal transduction, as compared to when more ubiquitous promoters are used (i.e., CBA or CMV).

In some embodiments, the AAV serotype is a serotype comprising the AAVPHP.N (PHP.N) peptide, or a variant thereof.

In some embodiments the AAV serotype is a serotype comprising the AAVPHP.B (PHP.B) peptide, or a variant thereof.

In some embodiments, the AAV serotype is a serotype comprising the AAVPHP.A (PHP.A) peptide, or a variant thereof.

In some embodiments, the AAV serotype is a serotype comprising the PHP.S peptide, or a variant thereof.

In some embodiments, the AAV serotype is a serotype comprising the PHP.B2 peptide, or a variant thereof.

In some embodiments, the AAV serotype is a serotype comprising the PHP.B3 peptide, or a variant thereof.

In some embodiments, the AAV serotype is a serotype comprising the G2B4 peptide, or a variant thereof.

In some embodiments, the AAV serotype is a serotype comprising the G2B5 peptide, or a variant thereof.

In some embodiments the AAV serotype is VOY101, or a variant thereof. In some embodiments, the VOY101 capsid comprises the amino acid sequence SEQ ID NO: 1. In some embodiments, the VOY101 amino acid sequence is encoded by a nucleotide sequence comprising SEQ ID NO: 2. In some embodiments, the VOY101 capsid comprises an amino acid sequence at least 70% identical to SEQ ID NO: 1, such as, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater than 99%. In some embodiments, the VOY101 capsid comprises a nucleotide sequence at least 70% identical to SEQ ID NO: 2, such as, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater than 99%.

In some embodiments, the AAV serotype is VOY201, or a variant thereof. In some embodiments, the VOY201 capsid comprises the amino acid sequence SEQ ID NO: 4534. In some embodiments, the VOY201 amino acid sequence is encoded by a nucleotide sequence comprising SEQ ID NO: 3. In some embodiments, the VOY201 capsid comprises an amino acid sequence at least 70% identical to SEQ ID NO: 4534, such as, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater than 99%. In some embodiments, the VOY201 capsid comprises a nucleotide sequence at least 70% identical to SEQ ID NO: 3, such as, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater than 99%.

In some embodiments, the AAV serotype is PHP.B, or a variant thereof. In some embodiments, the PHP.B capsid comprises the amino acid sequence SEQ ID NO: 5. In some embodiments, the PHP.B amino acid sequence is encoded by a nucleotide sequence comprising SEQ ID NO: 6. In some embodiments, the PHP.B capsid comprises an amino acid sequence at least 70% identical to SEQ ID NO: 5, such as, 70%, 75%, 80%, 85/6, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater than 99%. In some embodiments, the PHP.B capsid comprises a nucleotide sequence at least 70% identical to SEQ ID NO: 6, such as, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater than 99%.

In some embodiments, the AAV serotype is PHP.N, or a variant thereof. In some embodiments, the PHP.N capsid comprises the amino acid sequence SEQ ID NO: 4. In some embodiments, the PHP.N capsid comprises an amino acid sequence at least 70% identical to SEQ ID NO: 4, such as, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater than 99%.

In some embodiments the AAV serotype is AAV9, or a variant thereof. In some embodiments, the AAV9 capsid comprises the amino acid sequence SEQ ID NO: 138. In some embodiments, the AAV9 amino acid sequence is encoded by a nucleotide sequence comprising SEQ ID NO: 137. In some embodiments, the AAV9 capsid comprises an amino acid sequence at least 70% identical to SEQ ID NO: 138, such as, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater than 99%. In some embodiments, the AAV9 capsid comprises a nucleotide sequence at least 70% identical to SEQ ID NO: 137, such as, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater than 99%.

In some embodiments, the AAV serotype is AAV9K449R, or a variant thereof. In some embodiments, the AAV9K449R capsid comprises the amino acid sequence SEQ ID NO: 11. In some embodiments, the AAV9K449R capsid comprises an amino acid sequence at least 70% identical to SEQ ID NO: 11, such as, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater than 99%.

In some embodiments, the AAV capsid allows for blood brain barrier penetration following intravenous administration. Non-limiting examples of such AAV capsids include AAV9, AAV9K449R, VOY101, VOY201, or AAV capsids comprising a peptide insert such as, but not limited to, AAVPHP.N (PHP.N), AAVPHP.B (PHP.B), PHP.S, G2A3, G2B4, G2B5, G2A12, G2A15, PHP.B2, PHP.B3, or AAVPHP.A (PHP.A).

In some embodiments, the AAV capsid is suitable for intramuscular administration and/or transduction of muscle fibers. Non-limiting examples of such AAV capsids include AAV2, AAV3, AAV8 and variants thereof such as, but not limited to, AAV2 variants, AAV2/3 variants, AAV8 variants, and/or AAV2/3/8 variants.

In some embodiments, the AAV serotype is an AAV2 variant. As a non-limiting example, the AAV serotype is an AAV2 variant comprising SEQ ID NO: 2679 or a fragment or variant thereof. As a non-limiting example, the AAV serotype is at least 70% identical to SEQ ID NO: 2679, such as, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater than 99%.

In some embodiments, the AAV serotype is an AAV2/3 variant. As a non-limiting example, the AAV serotype is an AAV2/3 variant comprising SEQ ID NO: 2809 or a fragment or variant thereof. As a non-limiting example, the AAV serotype is an AAV2/3 variant which is at least 70% identical to SEQ ID NO: 2809, such as, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater than 99%. As a non-limiting example, the AAV serotype is an AAV2/3 variant comprising SEQ ID NO: 2871 or a fragment or variant thereof. As a non-limiting example, the AAV serotype is an AAV2/3 variant which is at least 70% identical to SEQ ID NO: 2871, such as, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater than 99%.

In some embodiments, the AAV serotype may comprise a capsid amino acid sequence with 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any of those described herein.

In some embodiments, the AAV serotype may be encoded by a capsid nucleic acid sequence with 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any of those described herein.

In some embodiments, the AAV serotype is selected for use due to its tropism for cells of the central nervous system. In some embodiments, the cells of the central nervous system are neurons. In another embodiment, the cells of the central nervous system are astrocytes.

In some embodiments, the AAV serotype is selected for use due to its tropism for cells of the muscle(s).

In some embodiments, the initiation codon for translation of the AAV VP1 capsid protein may be CTG, TTG, or GTG as described in U.S. Pat. No. 8,163,543, the contents of which are herein incorporated by reference in its entirety.

The present disclosure refers to structural capsid proteins (including VP1, VP2 and VP3) which are encoded by capsid (Cap) genes. These capsid proteins form an outer protein structural shell (i.e. capsid) of a viral vector such as AAV. VP capsid proteins synthesized from Cap polynucleotides generally include a methionine as the first amino acid in the peptide sequence (Met1), which is associated with the start codon (AUG or ATG) in the corresponding Cap nucleotide sequence. However, it is common for a first-methionine (Met1) residue or generally any first amino acid (AA1) to be cleaved off after or during polypeptide synthesis by protein processing enzymes such as Met-aminopeptidases. This “Met/AA-clipping” process often correlates with a corresponding acetylation of the second amino acid in the polypeptide sequence (e.g., alanine, valine, serine, threonine, etc.). Met-clipping commonly occurs with VP1 and VP3 capsid proteins but can also occur with VP2 capsid proteins.

Where the Met/AA-clipping is incomplete, a mixture of one or more (one, two or three) VP capsid proteins comprising the viral capsid may be produced, some of which may include a Met1/AA1 amino acid (Met+/AA+) and some of which may lack a Met1/AA1 amino acid as a result of Met/AA-clipping (Met−/AA−). For further discussion regarding Met/AA-clipping in capsid proteins, see Jin, et al. Direct Liquid Chromatography/Mass Spectrometry Analysis for Complete Characterization of Recombinant Adeno-Associated Virus Capsid Proteins. Hum Gene Ther Methods. 2017 Oct. 28(5):255-267; Hwang, et al. N-Terminal Acetylation of Cellular Proteins Creates Specific Degradation Signals. Science. 2010 Feb. 19. 327(5968): 973-977; the contents of which are each incorporated herein by reference in its entirety.

According to the present disclosure, references to capsid proteins is not limited to either clipped (Met−/AA−) or unclipped (Met+/AA+) and may, in context, refer to independent capsid proteins, viral capsids comprised of a mixture of capsid proteins, and/or polynucleotide sequences (or fragments thereof) which encode, describe, produce or result in capsid proteins of the present disclosure. A direct reference to a “capsid protein” or “capsid polypeptide” (such as VP1, VP2 or VP2) may also comprise VP capsid proteins which include a Met1/AA1 amino acid (Met+/AA+) as well as corresponding VP capsid proteins which lack the Met1/AA1 amino acid as a result of Met/AA-clipping (Met−/AA−).

Further according to the present disclosure, a reference to a specific SEQ ID NO: (whether a protein or nucleic acid) which comprises or encodes, respectively, one or more capsid proteins which include a Met1/AA1 amino acid (Met+/AA+) should be understood to teach the VP capsid proteins which lack the Met1/AA1 amino acid as upon review of the sequence, it is readily apparent any sequence which merely lacks the first listed amino acid (whether or not Met1/AA1).

As a non-limiting example, reference to a VP1 polypeptide sequence which is 736 amino acids in length and which includes a “Met1” amino acid (Met+) encoded by the AUG/ATG start codon may also be understood to teach a VP1 polypeptide sequence which is 735 amino acids in length and which does not include the “Met1” amino acid (Met−) of the 736 amino acid Met+ sequence. As a second non-limiting example, reference to a VP1 polypeptide sequence which is 736 amino acids in length and which includes an “AA1” amino acid (AA1+) encoded by any NNN initiator codon may also be understood to teach a VP1 polypeptide sequence which is 735 amino acids in length and which does not include the “AA1” amino acid (AA1−) of the 736 amino acid AA1+ sequence.

References to viral capsids formed from VP capsid proteins (such as reference to specific AAV capsid serotypes), can incorporate VP capsid proteins which include a Met1/AA1 amino acid (Met+/AA1+), corresponding VP capsid proteins which lack the Met1/AA1 amino acid as a result of Met/AA1-clipping (Met−/AA1−), and combinations thereof (Met+/AA1+ and Met−/AA1−).

As a non-limiting example, an AAV capsid serotype can include VP1 (Met+/AA1+), VP1 (Met−/AA1−), or a combination of VP1 (Met+/AA1+) and VP1 (Met−/AA1−). An AAV capsid serotype can also include VP3 (Met+/AA1+), VP3 (Met−/AA1−), or a combination of VP3 (Met+/AA1+) and VP3 (Met−/AA1−); and can also include similar optional combinations of VP2 (Met+/AA1) and VP2 (Met−/AA1−).

Viral Genome Component: Inverted Terminal Repeals (ITRs)

The AAV particles of the present disclosure comprise a viral genome with at least one ITR region and a payload region. In some embodiments, the viral genome has two ITRs. These two ITRs flank the payload region at the 5′ and 3′ ends. The ITRs function as origins of replication comprising recognition sites for replication. ITRs comprise sequence regions which can be complementary and symmetrically arranged. ITRs incorporated into viral genomes may be comprised of naturally occurring polynucleotide sequences or recombinantly derived polynucleotide sequences.

The ITRs may be derived from the same serotype as the capsid, selected from any of the serotypes listed in Table 1, or a derivative thereof. The ITR may be of a different serotype than the capsid. In some embodiments, the AAV particle has more than one ITR. In a non-limiting example, the AAV particle has a viral genome comprising two ITRs. In some embodiments, the ITRs are of the same serotype as one another. In another embodiment, the ITRs are of different serotypes. Non-limiting examples include zero, one or both of the ITRs having the same serotype as the capsid. In some embodiments both ITRs of the viral genome of the AAV particle are AAV2 ITRs.

Independently, each ITR may be about 100 to about 150 nucleotides in length. An ITR may be about 100-105 nucleotides in length, 106-110 nucleotides in length, 111-115 nucleotides in length, 116-120 nucleotides in length, 121-125 nucleotides in length, 126-130 nucleotides in length, 131-135 nucleotides in length, 136-140 nucleotides in length, 141-145 nucleotides in length or 146-150 nucleotides in length. In some embodiments, the ITRs are 140-142 nucleotides in length. Non-limiting examples of ITR length are 102, 130, 140, 141, 142, 145 nucleotides in length, and those having at least 95% identity thereto.

In some embodiments, each ITR may be 141 nucleotides in length.

In some embodiments, each ITR may be 130 nucleotides in length.

In some embodiments, the AAV particles comprise two ITRs and one ITR is 141 nucleotides in length and the other ITR is 130 nucleotides in length.

Viral Genome Component: Promoters

In some embodiments, the payload region of the viral genome comprises at least one element to enhance the transgene target specificity and expression (See e.g., Powell et al. Viral Expression Cassette Elements to Enhance Transgene Target Specificity and Expression in Gene Therapy, 2015; the contents of which are herein incorporated by reference in its entirety). Non-limiting examples of elements to enhance the transgene target specificity and expression include promoters, endogenous miRNAs, post-transcriptional regulatory elements (PREs), polyadenylation (PolyA) signal sequences and upstream enhancers (USEs), CMV enhancers and introns.

A person skilled in the art may recognize that expression of the polypeptides in a target cell may require a specific promoter, including but not limited to, a promoter that is species specific, inducible, tissue-specific, or cell cycle-specific (Parr et al., Nat. Med 3:1145-9 (1997); the contents of which are herein incorporated by reference in their entirety).

In some embodiments, the promoter is deemed to be efficient when it drives expression of the polypeptide(s) encoded in the payload region of the viral genome of the AAV particle.

In some embodiments, the promoter is a promoter deemed to be efficient when it drives expression in the cell being targeted.

In some embodiments, the promoter drives expression of the polypeptides (e.g., a functional antibody) for a period of time in targeted tissues. Expression driven by a promoter may be for a period of 1 hour, 2, hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 3 weeks, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years or more than 10 years. Expression may be for 1-5 hours, 1-12 hours, 1-2 days, 1-5 days, 1-2 weeks, 1-3 weeks, 1-4 weeks, 1-2 months, 1-4 months, 1-6 months, 2-6 months, 3-6 months, 3-9 months, 4-8 months, 6-12 months, 1-2 years, 1-5 years, 2-5 years, 3-6 years, 3-8 years, 4-8 years, or 5-10 years.

In some embodiments, the promoter drives expression of the polypeptides (e.g., a functional antibody) for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 1 years, 12 years, 13 years, 14 years, 15 years, 16 years, 17 years, 18 years, 19 years, 20 years, 21 years, 22 years, 23 years, 24 years, 25 years, 26 years, 27 years, 28 years, 29 years, 30 years, 31 years, 32 years, 33 years, 34 years, 35 years, 36 years, 37 years, 38 years, 39 years, 40 years, 41 years, 42 years, 43 years, 44 years, 45 years, 46 years, 47 years, 48 years, 49 years, 50 years, 55 years, 60 years, 65 years, or more than 65 years.

Promoters may be naturally occurring or non-naturally occurring. Non-limiting examples of promoters include viral promoters, plant promoters and mammalian promoters. In some embodiments, the promoters may be human promoters. In some embodiments, the promoter may be truncated.

Promoters which drive or promote expression in most tissues include, but are not limited to, human elongation factor 1α-subunit (EF1α), cytomegalovirus (CMV) immediate-early enhancer and/or promoter, chicken β-actin (CBA) and its derivative CAG, β glucuronidase (GUSB), or ubiquitin C (UBC). Tissue-specific expression elements can be used to restrict expression to certain cell types such as, but not limited to, muscle specific promoters. B cell promoters, monocyte promoters, leukocyte promoters, macrophage promoters, pancreatic acinar cell promoters, endothelial cell promoters, lung tissue promoters, astrocyte promoters, or nervous system promoters which can be used to restrict expression to neurons, astrocytes, or oligodendrocytes.

Non-limiting examples of muscle-specific promoters include mammalian muscle creatine kinase (MCK) promoter, mammalian desmin (DES) promoter, mammalian troponin I (TNNI2) promoter, and mammalian skeletal alpha-actin (ASKA) promoter (see, e.g. U.S. Patent Publication US20110212529, the contents of which are herein incorporated by reference in their entirety)

Non-limiting examples of tissue-specific expression elements for neurons include neuron-specific enolase (NSE), platelet-derived growth factor (PDGF), platelet-derived growth factor B-chain (PDGF-β), synapsin (Syn), methyl-CpG binding protein 2 (MeCP2), Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), metabotropic glutamate receptor 2 (mGluR2), neurofilament light (NFL) or heavy (NFH), β-globin minigene nβ2, preproenkephalin (PPE), enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2) promoters. Non-limiting examples of tissue-specific expression elements for astrocytes include glial fibrillary acidic protein (GFAP) and EAAT2 promoters. A non-limiting example of a tissue-specific expression element for oligodendrocytes includes the myelin basic protein (MBP) promoter.

In some embodiments, the promoter may be less than 1 kb. The promoter may have a length of 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, or more than 800 nucleotides. The promoter may have a length between 200-300, 200-400, 200-500, 200-600, 200-700, 200-800, 300-400, 300-500, 300-600, 300-700, 300-800, 400-500, 400-600, 400-700, 400-800, 500-600, 500-700, 500-800, 600-700, 600-800, or 700-800.

In some embodiments, the promoter may be a combination of two or more components of the same or different starting or parental promoters such as, but not limited to, CMV and CBA. Each component may have a length of 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350,360, 370, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, or more than 800. Each component may have a length between 200-300, 200-400, 200-500, 200-600, 200-700, 200-800, 300-400, 300-500, 300-600, 300-700, 300-800, 400-500, 400-600, 400-700, 400-800, 500-600, 500-700, 500-800, 600-700, 600-800 or 700-800. In some embodiments, the promoter is a combination of a 382 nucleotide CMV-enhancer sequence and a 260 nucleotide CBA-promoter sequence.

In some embodiments, the viral genome comprises a ubiquitous promoter. Non-limiting examples of ubiquitous promoters include CMV, CBA (including derivatives CAG, CB6, CBh, etc.), EF-1α, PGK, UBC, GUSB (hGBp), and UCOE (promoter of HNRPA2B1-CBX3).

Yu et al. (Molecular Pain 2011, 7:63; the contents of which are herein incorporated by reference in their entirety) evaluated the expression of eGFP under the CAG, EF1α, PGK and UBC promoters in rat DRG cells and primary DRG cells using lentiviral vectors and found that UBC showed weaker expression than the other 3 promoters and only 10-12% glial expression was seen for all promoters. Soderblom et al. (E. Neuro 2015; the contents of which are herein incorporated by reference in its entirety) evaluated the expression of eGFP in AAV8 with CMV and UBC promoters and AAV2 with the CMV promoter after injection in the motor cortex. Intranasal administration of a plasmid containing a UBC or EF1α promoter showed a sustained airway expression greater than the expression with the CMV promoter (See e.g., Gill et al., Gene Therapy 2001, Vol. 8, 1539-1546; the contents of which are herein incorporated by reference in their entirety). Husain et al. (Gene Therapy 2009; the contents of which are herein incorporated by reference in its entirety) evaluated an HOH construct with a hGUSB promoter, an HSV-1LAT promoter and an NSE promoter and found that the HOH construct showed weaker expression than NSE in mouse brain. Passini and Wolfe (J. Virol. 2001, 12382-12392, the contents of which are herein incorporated by reference in its entirety) evaluated the long-term effects of the HOH vector following an intraventricular injection in neonatal mice and found that there was sustained expression for at least 1 year. Low expression in all brain regions was found by Xu et al. (Gene Therapy 2001, 8, 1323-1332; the contents of which are herein incorporated by reference in their entirety) when NFL and NFH promoters were used as compared to the CMV-lacZ, CMV-luc, EF, GFAP, hENK, nAChR, PPE, PPE+wpre, NSE (0.3 kb), NSE (1.8 kb) and NSE (1.8 kb+wpre). Xu et al. found that the promoter activity in descending order was NSE (1.8 kb), EF, NSE (0.3 kb), GFAP, CMV, hENK, PPE, NFL and NFH. NFL is a 650 nucleotide promoter and NFH is a 920-nucleotide promoter which are both absent in the liver but NFH is abundant in the sensory proprioceptive neurons, brain and spinal cord and NFH is present in the heart. Scn8a is a 470 nucleotide promoter which expresses throughout the DRG, spinal cord and brain with particularly high expression seen in the hippocampal neurons and cerebellar Purkinje cells, cortex, thalamus, and hypothalamus (See e.g., Drews et al. Identification of evolutionary conserved, functional noncoding elements in the promoter region of the sodium channel gene SCN8A. Mamm Genome (2007) 18:723-731; and Raymond et al. Expression of Alternatively Spliced Sodium Channel α-subunit genes. Journal of Biological Chemistry (2004) 279(44) 46234-46241; the contents of each of which are herein incorporated by reference in their entireties).

Any of promoters taught by the aforementioned Yu, Soderblom, Gill, Husain. Passini, Xu, Drews, or Raymond may be used in the present disclosures.

In some embodiments, the promoter is not cell specific.

In some embodiments, the promoter is a ubiquitin c (UBC) promoter. The UBC promoter may have a size of 300-350 nucleotides. As a non-limiting example, the UBC promoter is 332 nucleotides.

In some embodiments, the promoter is a β-glucuronidase (GUSB) promoter. The GUSB promoter may have a size of 350-400 nucleotides. As a non-limiting example, the GUSB promoter is 378 nucleotides.

In some embodiments, the promoter is a neurofilament light (NFL) promoter. The NFL promoter may have a size of 600-700 nucleotides. As a non-limiting example, the NFL promoter is 650 nucleotides.

In some embodiments, the promoter is a neurofilament heavy (NFH) promoter. The NFH promoter may have a size of 900-950 nucleotides. As a non-limiting example, the NFH promoter is 920 nucleotides.

In some embodiments, the promoter is a scn8a promoter. The scn8a promoter may have a size of 450-500 nucleotides. As a non-limiting example, the scn8a promoter is 470 nucleotides.

In some embodiments, the promoter is a phosphoglycerate kinase 1 (PGK) promoter.

In some embodiments, the promoter is a chicken β-actin (CBA) promoter, or a variant thereof.

In some embodiments, the promoter is a CB6 promoter.

In some embodiments, the promoter is a minimal CB promoter.

In some embodiments, the promoter is a cytomegalovirus (CMV) promoter.

In some embodiments, the promoter is a CAG promoter.

In some embodiments, the promoter is a GFAP promoter.

In some embodiments, the promoter is a synapsin promoter.

In some embodiments, the promoter is a liver or a skeletal muscle promoter. Non-limiting examples of liver promoters include human α-1-antitrypsin (hAAT) and thyroxine binding globulin (TBG). Non-limiting examples of skeletal muscle promoters include Desmin, MCK or synthetic CS-12.

In some embodiments, the promoter is an RNA pol III promoter. As a non-limiting example, the RNA pol III promoter is U6. As a non-limiting example, the RNA pol III promoter is H1.

In some embodiments, the viral genome comprises two promoters. As a non-limiting example, the promoters are an EF1α promoter and a CMV promoter.

In some embodiments, the viral genome comprises an enhancer element, a promoter and/or a 5′UTR intron. The enhancer element, also referred to herein as an “enhancer,” may be, but is not limited to, a CMV enhancer, the promoter may be, but is not limited to, a CMV, CBA, UBC, GUSB, NSE, Synapsin, MeCP2, and GFAP promoter and the 5′UTR/intron may be, but is not limited to, SV40, and CBA-MVM. As a non-limiting example, the enhancer, promoter and/or intron used in combination may be: (1) CMV enhancer, CMV promoter, SV40 5′UTR intron; (2) CMV enhancer, CBA promoter, SV 40 5′UTR intron; (3) CMV enhancer, CBA promoter, CBA-MVM 5′UTR intron; (4) UBC promoter; (5) GUSB promoter; (6) NSE promoter; (7) Synapsin promoter; (8) MeCP2 promoter; and (9) GFAP promoter.

In some embodiments, the viral genome comprises an engineered promoter.

In another embodiment, the viral genome comprises a promoter from a naturally expressed protein.

Viral Genome Component: Untranslated Regions (UTRs)

By definition, wild type untranslated regions (UTRs) of a gene are transcribed but not translated. Generally, the 5′ UTR starts at the transcription start site and ends at the start codon and the 3′ UTR starts immediately following the stop codon and continues until the termination signal for transcription.

Features typically found in abundantly expressed genes of specific target organs may be engineered into UTRs to enhance the stability and protein production. As a non-limiting example, a 5′ UTR from mRNA normally expressed in the liver (e.g., albumin, serum amyloid A, Apolipoprotein A/B/E, transferrin, alpha fetoprotein, erythropoietin, or Factor VIII) may be used in the viral genomes of the AAV particles to enhance expression in hepatic cell lines or liver.

While not wishing to be bound by theory, wild-type 5′ untranslated regions (UTRs) include features which play roles in translation initiation. Kozak sequences, which are commonly known to be involved in the process by which the ribosome initiates translation of many genes, are usually included in 5′ UTRs. Kozak sequences have the consensus CCR(A/G)CCAUGG, where R is a purine (adenine or guanine) three bases upstream of the start codon (ATG), which is followed by another ‘G’.

In some embodiments, the 5′UTR in the viral genome includes a Kozak sequence.

In some embodiments, the 5′UTR in the viral genome does not include a Kozak sequence.

In some embodiments, the Kozak sequence is GAGGAGCCACC (SEQ ID NO: 4543).

In some embodiments, the Kozak sequence is GCCGCCACCATG (SEQ ID NO: 2114)

While not wishing to be bound by theory, wild-type 3′ UTRs are known to have stretches of Adenosines and Uridines embedded therein. These AU rich signatures are particularly prevalent in genes with high rates of turnover. Based on their sequence features and functional properties, the AU rich elements (AREs) can be separated into three classes (Chen et al, 1995, the contents of which are herein incorporated by reference in its entirety): Class I AREs, such as, but not limited to, c-Myc and MyoD, contain several dispersed copies of an AUUUA motif within U-rich regions. Class II AREs, such as, but not limited to, GM-CSF and TNF-a, possess two or more overlapping UUAUUUA(U/A)(U/A) nonamers. Class III ARES, such as, but not limited to, c-Jun and Myogenin, are less well defined. These U rich regions do not contain an AUUUA motif. Most proteins binding to the AREs are known to destabilize the messenger, whereas members of the ELAV family, most notably HuR, have been documented to increase the stability of mRNA. HuR binds to AREs of all the three classes. Engineering the HuR specific binding sites into the 3′ UTR of nucleic acid molecules will lead to HuR binding and thus, stabilization of the message in vivo.

Introduction, removal or modification of 3′ UTR AU rich elements (AREs) can be used to modulate the stability of polynucleotides. When engineering specific polynucleotides, e.g., payload regions of viral genomes, one or more copies of an ARE can be introduced to make polynucleotides less stable and thereby curtail translation and decrease production of the resultant protein. Likewise, AREs can be identified and removed or mutated to increase the intracellular stability and thus increase translation and production of the resultant protein.

In some embodiments, the 3′ UTR of the viral genome may include an oligo(dT) sequence for templated addition of a poly-A tail.

In some embodiments, the viral genome may include at least one miRNA seed, binding site or full sequence, microRNAs (or miRNA or miR) are 19-25 nucleotide noncoding RNAs that bind to the sites of nucleic acid targets and down-regulate gene expression either by reducing nucleic acid molecule stability or by inhibiting translation. A microRNA sequence comprises a “seed” region, i.e., a sequence in the region of positions 2-8 of the mature microRNA, which sequence has perfect Watson-Crick complementarity to the miRNA target sequence of the nucleic acid.

In some embodiments, the viral genome may be engineered to include, alter or remove at least one miRNA binding site, sequence, or seed region.

Any UTR from any gene known in the art may be incorporated into the viral genome of the AAV particle. These UTRs, or portions thereof, may be placed in the same orientation as in the gene from which they were selected, or they may be altered in orientation or location. In some embodiments, the UTR used in the viral genome of the AAV particle may be inverted, shortened, lengthened, made with one or more other 5′ UTRs or 3′ UTRs known in the art. As used herein, the term “altered” as it relates to a UTR, means that the UTR has been changed in some way in relation to a reference sequence. For example, a 3′ or 5′ UTR may be altered relative to a wild type or native UTR by the change in orientation or location as taught above or may be altered by the inclusion of additional nucleotides, deletion of nucleotides, swapping or transposition of nucleotides.

In some embodiments, the viral genome of the AAV particle comprises at least one artificial UTRs which is not a variant of a wild type UTR.

In some embodiments, the viral genome of the AAV particle comprises UTRs which have been selected from a family of transcripts whose proteins share a common function, structure, feature or property.

Viral Genome Component: Polyadenylation Sequence

In some embodiments, the viral genome of the AAV particles of the present disclosure comprise at least one polyadenylation sequence. The viral genome of the AAV particle may comprise a polyadenylation sequence between the 3′ end of the payload coding sequence and the 5′ end of the 3′ITR.

In some embodiments, the polyadenylation sequence or “polyA sequence” may range from absent to about 500 nucleotides in length. The polyadenylation sequence may be, but is not limited to, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, and 600 nucleotides in length.

In some embodiments, the polyadenylation sequence is 50-100 nucleotides in length.

In some embodiments, the polyadenylation sequence is 50-150 nucleotides in length.

In some embodiments, the polyadenylation sequence is 50-160 nucleotides in length.

In some embodiments, the polyadenylation sequence is 50-200 nucleotides in length.

In some embodiments, the polyadenylation sequence is 60-100 nucleotides in length.

In some embodiments, the polyadenylation sequence is 60-150 nucleotides in length.

In some embodiments, the polyadenylation sequence is 60-160 nucleotides in length.

In some embodiments, the polyadenylation sequence is 60-200 nucleotides in length.

In some embodiments, the polyadenylation sequence is 70-100 nucleotides in length.

In some embodiments, the polyadenylation sequence is 70-150 nucleotides in length.

In some embodiments, the polyadenylation sequence is 70-160 nucleotides in length.

In some embodiments, the polyadenylation sequence is 70-200 nucleotides in length.

In some embodiments, the polyadenylation sequence is 80-100 nucleotides in length.

In some embodiments, the polyadenylation sequence is 80-150 nucleotides in length.

In some embodiments, the polyadenylation sequence is 80-160 nucleotides in length.

In some embodiments, the polyadenylation sequence is 80-200 nucleotides in length.

In some embodiments, the polyadenylation sequence is 90-100 nucleotides in length.

In some embodiments, the polyadenylation sequence is 90-150 nucleotides in length.

In some embodiments, the polyadenylation sequence is 90-160 nucleotides in length.

In some embodiments, the polyadenylation sequence is 90-200 nucleotides in length.

In some embodiments, the polyadenylation sequence is 127 nucleotides in length.

In some embodiments, the polyadenylation sequence is 477 nucleotides in length.

In some embodiments, the polyadenylation sequence is 552 nucleotides in length.

Viral Genome Component: Linkers

Viral genomes may be engineered with one or more spacer or linker regions to separate coding or non-coding regions.

In some embodiments, the payload region of the AAV particle may optionally encode one or more linker sequences. In some cases, the linker may be a peptide linker that may be used to connect the polypeptides encoded by the payload region (i.e., light and heavy antibody chains during expression). Some peptide linkers may be cleaved after expression to separate heavy and light chain domains, allowing assembly of mature antibodies or antibody fragments. Linker cleavage may be enzymatic. In some cases, linkers comprise an enzymatic cleavage site to facilitate intracellular or extracellular cleavage. Some payload regions encode linkers that interrupt polypeptide synthesis during translation of the linker sequence from an mRNA transcript. Such linkers may facilitate the translation of separate protein domains (e.g., heavy and light chain antibody domains) from a single transcript. In some cases, two or more linkers are encoded by a payload region of the viral genome. Non-limiting examples of linkers that may be encoded by the payload region of an AAV particle viral genome are given in Table 2.

TABLE 2 Linkers Linker ID Description Length SEQ ID NO Linker1 Furin 12 1724 Linker2 Furin 12 1725 Linker3 T2A 54 1726 Linker4 F2A 75 1727 Linker5 P2A 66 1728 Linker6 SG4S (SEQ ID NO: 4536) 18 1729 Linker7 (G4S)3 (SEQ ID NO: 4537) 45 1730 Linker8 (G4S)5 (SEQ ID NO: 4538) 75 1731 Linker9 IRES 609 1732 Linker10 IRES-2 623 1733 Linker11 hIgG2 hinge 54 1734 Linker12 hIgG3 hinge 108 1735 Linker13 hIgG3-2 hinge 153 1736 Linker14 hIgG3-3 hinge 198 1737 Linker15 msiGG-1 hinge 45 1738 Linker16 msiGG1 hinge 18 1739 Linker17 HigG3 hinge 198 2244 Linker18 G4S (SEQ ID NO: 4535) 15 2245 Linker19 (G4S)2 (SEQ ID NO: 4539) 30 2246 Linker20 (G4S)3 (SEQ ID NO: 4537) 45 2247 Linker21 (G4S)4 (SEQ ID NO: 4540) 60 2248 Linker22 (G4S)5 (SEQ ID NO: 4538) 75 2249 Linker23 (G4S)5 (SEQ ID NO: 4538) 75 2250 Linker24 (G4S)6 (SEQ ID NO: 4541) 90 2251 Linker25 (G4S)8 (SEQ ID NO: 4542) 120 2252 Linker26 (G4S)8 (SEQ ID NO: 4542) 120 2253 Linker27 (G4S)4 (SEQ ID NO: 4540) 60 2254 Linker28 (G4S)6 (SEQ ID NO: 4541) 90 2259

Some payload regions encode linkers comprising furin cleavage sites. Furin is a calcium dependent serine endoprotease that cleaves proteins just downstream of a basic amino acid target sequence (Arg-X-(Arg/Lys)-Arg) (Thomas, G., 2002. Nature Reviews Molecular Cell Biology 3(10): 753-66; the contents of which are herein incorporated by reference in its entirety). Furin is enriched in the trans-golgi network where it is involved in processing cellular precursor proteins. Furin also plays a role in activating a number of pathogens. This activity can be taken advantage of for expression of polypeptides.

2A peptides are small “self-cleaving” peptides (18-22 amino acids) derived from viruses such as foot-and-mouth disease virus (F2A), porcine teschovirus-1 (P2A), Thoseaasigna virus (T2A), or equine rhinitis A virus (E2A). The 2A designation refers specifically to a region of picornavirus polyproteins that lead to a ribosomal skip at the glycyl-prolyl bond in the C-terminus of the 2A peptide (Kim, J. H. et al., 2011. PLoS One 6(4): e18556; the contents of which are herein incorporated by reference in its entirety). This skip results in a cleavage between the 2A peptide and its immediate downstream peptide. As opposed to IRES linkers, 2A peptides generate stoichiometric expression of proteins flanking the 2A peptide and their shorter length can be advantageous in generating viral expression vectors.

Internal ribosomal entry site (IRES) is a nucleotide sequence (>500 nucleotides) that allows for initiation of translation in the middle of an mRNA sequence (Kim, J. H. et al., 2011. PLoS One 6(4): e18556; the contents of which are herein incorporated by reference in its entirety). Use of an IRES sequence ensures co-expression of genes before and after the IRES, though the sequence following the IRES may be transcribed and translated at lower levels than the sequence preceding the IRES sequence.

In some embodiments, the payload region may encode one or more linkers comprising cathepsin, matrix metalloproteinases or legumain cleavage sites. Such linkers are described e.g. by Cizeau and Macdonald in International Publication No. WO2008052322, the contents of which are herein incorporated in their entirety. Cathepsins are a family of proteases with unique mechanisms to cleave specific proteins. Cathepsin B is a cysteine protease and cathepsin D is an aspartyl protease. Matrix metalloproteinases are a family of calcium-dependent and zinc-containing endopeptidases. Legumain is an enzyme catalyzing the hydrolysis of (-Asn-Xaa-) bonds of proteins and small molecule substrates.

In some embodiments, payload regions may encode linkers that are not cleaved. Such linkers may include a simple amino acid sequence, such as a glycine rich sequence. In some cases, linkers may comprise flexible peptide linkers comprising glycine and serine residues. The linker may comprise flexible peptide linkers of different lengths, e.g. nxG4S, where n=1-10 (SEQ ID NO: 4544), and the length of the encoded linker varies between 5 and 50 amino acids. In a non-limiting example, the linker may be 5xG4S (SEQ ID NO: 4544). These flexible linkers are small and without side chains so they tend not to influence secondary protein structure while providing a flexible linker between antibody segments (George, R. A., et al., 2002. Protein Engineering 15(11): 871-9; Huston, J. S. et al., 1988. PNAS 85:5879-83; and Shan, D. et al., 1999. Journal of Immunology. 162(11):6589-95; the contents of each of which are herein incorporated by reference in their entirety). Furthermore, the polarity of the serine residues improves solubility and prevents aggregation problems.

In some embodiments, payload regions may encode small and unbranched serine-rich peptide linkers, such as those described by Huston et al. in U.S. Pat. No. 5,525,491, the contents of which are herein incorporated in their entirety. Polypeptides encoded by the payload region, linked by serine-rich linkers, have increased solubility.

In some embodiments, payload regions may encode artificial linkers, such as those described by Whitlow and Filpula in U.S. Pat. No. 5,856,456 and Ladner et al. in U.S. Pat. No. 4,946,778, the contents of each of which are herein incorporated by their entirety.

In some embodiments, the payload region encodes at least one G4S3 linker (“G4S3” disclosed as SEQ ID NO: 4537).

In some embodiments, the payload region encodes at least one G4S linker (“G4S” disclosed as SEQ ID NO: 4535).

In some embodiments, the payload region encodes at least one furin site.

In some embodiments, the payload region encodes at least one T2A linker.

In some embodiments, the payload region encodes at least one F2A linker.

In some embodiments, the payload region encodes at least one P2A linker.

In some embodiments, the payload region encodes at least one IRES sequence.

In some embodiments, the payload region encodes at least one G4S5 linker (“G4S5” disclosed as SEQ ID NO: 4538).

In some embodiments, the payload region encodes at least one furin and one 2A linker. As non-limiting examples, the payload region may comprise furin and T2A linkers or furin and F2A linkers.

In some embodiments, the payload region encodes at least one hinge region. As a non-limiting example, the hinge is an IgG hinge.

In some embodiments, the linker region may be 1-50, 1-100, 50-100, 50-150, 100-150, 100-200, 150-200, 150-250, 200-250, 200-300, 250-300, 250-350, 300-350, 300-400, 350-400, 350-450, 400-450, 400-500, 450-500, 450-550, 500-550, 500-600, 550-600, 550-650, or 600-650 nucleotides in length. The linker region may have a length of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 115, 120, 125, 130, 135, 140, 145, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 165, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 185, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 640, 650 or greater than 650. In some embodiments, the linker region may be 12 nucleotides in length. In some embodiments, the linker region may be 15 nucleotides in length, In some embodiments, the linker region may be 18 nucleotides in length. In some embodiments, the linker region may be 30 nucleotides in length. In some embodiments, the linker region may be 45 nucleotides in length. In some embodiments, the linker region may be 54 nucleotides in length. In some embodiments, the linker region may be 60 nucleotides in length. In some embodiments, the linker region may be 66 nucleotides in length. In some embodiments, the linker region may be 75 nucleotides in length. In some embodiments, the linker region may be 78 nucleotides in length. In some embodiments, the linker region may be 87 nucleotides in length. In some embodiments, the linker region may be 108 nucleotides in length. In some embodiments, the linker region may be 120 nucleotides in length. In some embodiments, the linker region may be 153 nucleotides in length. In some embodiments, the linker region may be 198 nucleotides in length. In some embodiments, the linker region may be 609 nucleotides in length. In some embodiments, the linker region may be 623 nucleotides in length.

Viral Genome Component: Introns

In some embodiments, the payload region comprises at least one element to enhance the expression such as one or more introns or portions thereof. Non-limiting examples of introns include, MVM (67-97 bps), F.IX truncated intron 1 (300 bps), 0-globin SD/immunoglobulin heavy chain splice acceptor (250 bps), adenovirus splice donor/immunoglobin splice acceptor (500 bps). SV40 late splice donor/splice acceptor (19S/16S) (180 bps) and hybrid adenovirus splice donor/IgG splice acceptor (230 bps).

In some embodiments, the intron or intron portion may be 1-100, 100-500, 500-1000, or 1000-1500 nucleotides in length. The intron may have a length of 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, or greater than 500. The intron may have a length between 80-100, 80-120, 80-140, 80-160, 80-180, 80-200, 80-250, 80-300, 80-350, 80-400, 80-450, 80-500, 200-300, 200-400, 200-500, 300-400, 300-500, or 400-500. In some embodiments, the intron may be 15 nucleotides in length. In some embodiments, the intron may be 32 nucleotides in length. In some embodiments, the intron may be 41 nucleotides in length. In some embodiments, the intron may be 53 nucleotides in length. In some embodiments, the intron may be 54 nucleotides in length. In some embodiments, the intron may be 59 nucleotides in length. In some embodiments, the intron may be 73 nucleotides in length. In some embodiments, the intron may be 102 nucleotides in length. In some embodiments, the intron may be 134 nucleotides in length. In some embodiments, the intron may be 168 nucleotides in length. In some embodiments, the intron may be 172 nucleotides in length. In some embodiments, the intron may be 292 nucleotides in length. In some embodiments, the intron may be 347 nucleotides in length. In some embodiments, the intron may be 387 nucleotides in length. In some embodiments, the intron may be 491 nucleotides in length. In some embodiments, the intron may be 566 nucleotides in length. In some embodiments, the intron may be 1074 nucleotides in length.

Any, or all components of a viral genome may be modified or optimized to improve expression or targeting of the payload. Such components include, but are not limited to, intron, signal peptide sequences, antibody heavy chain and/or light chain 5′ to 3′ order, antibody heavy chain and/or light chain codons, linkers, cleavage sites, polyadenylation sequences, stuffer sequences, other regulatory sequences, and/or the backbone of the ITR to ITR sequence.

Payloads

The AAV particles of the present disclosure comprise at least one payload region. As used herein, “payload” or “payload region” refers to one or more polynucleotides or polynucleotide regions encoded by or within a viral genome or an expression product of such polynucleotide or polynucleotide region, e.g., a transgene, a polynucleotide encoding a polypeptide or multi-polypeptide or a modulatory nucleic acid or regulatory nucleic acid. Payloads of the present disclosure typically encode polypeptides (e.g., antibodies or antibody-based compositions) or fragments or variants thereof.

The payload region may be constructed in such a way as to reflect a region similar to or mirroring the natural organization of an mRNA.

The payload region may comprise a combination of coding and non-coding nucleic acid sequences.

In some embodiments, the AAV payload region may encode a coding or non-coding RNA.

In some embodiments, the AAV particle comprises a viral genome with a payload region comprising nucleic acid sequences encoding more than one polypeptide of interest (e.g., an antibody). In such an embodiment, a viral genome encoding more than one polypeptide may be replicated and packaged into a viral particle. A target cell transduced with a viral particle comprising more than one polypeptide may express each of the polypeptides in a single cell.

In some embodiments, an AAV particle comprises a viral genome with a payload region comprising a nucleic acid sequence encoding a heavy chain and a light chain of an antibody, or fragments thereof. The heavy chain and light chain are expressed and assembled to form the antibody which is secreted.

In some embodiments, the payload region may comprise at least one inverted terminal repeat (ITR), a promoter region, an intron region, and a coding region. In some embodiments, the coding region comprises a heavy chain region and/or a light chain region of an antibody, or a fragment thereof, and any two components may be separated by a linker region.

In some embodiments, the coding region may comprise a payload region with a heavy chain and light chain sequence separated by a linker and/or a cleavage site. In some embodiments, the heavy and light chain sequence is separated by an IRES sequence. In some embodiments, the heavy and light chain sequence is separated by a foot and mouth virus sequence. In some embodiments, the heavy and light chain sequence is separated by a foot and mouth virus sequence and a furin cleavage site. In some embodiments, the heavy and light chain sequence is separated by a porcine teschovirus-1 virus sequence. In some embodiments, the heavy and light chain sequence is separated by a porcine teschovirus-1 virus and a furin cleavage site. In some embodiments, the heavy and light chain sequence is separated by a 5xG4S sequence (“5xG4S” disclosed as SEQ ID NO: 4538).

Where the AAV particle payload region encodes a polypeptide, the polypeptide may be a peptide or protein. A protein encoded by the AAV particle payload region may comprise an antibody, an antibody related composition, a secreted protein, an intracellular protein, an extracellular protein, and/or a membrane protein. The encoded proteins may be structural or functional. In addition to the antibodies or antibody-based composition, proteins encoded by the payload region may include, in combination, certain mammalian proteins involved in immune system regulation. The AAV viral genomes encoding polypeptides described herein may be useful in the fields of human disease, viruses, infections, veterinary applications and a variety of in vivo and in vitro settings.

In some embodiments, the AAV particles are useful in the field of medicine for the treatment, prophylaxis, palliation, or amelioration of neurological diseases and/or disorders.

Antibodies and Antibody-Based Compositions

Payload regions of the AAV particles may encode polypeptides that form one or more functional antibodies or antibody-based compositions. As used herein, the term “antibody” is referred to in the broadest sense and specifically covers various embodiments including, but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g. bispecific antibodies formed from at least two intact antibodies), and antibody fragments (e.g., diabodies) so long as they exhibit a desired biological activity (e.g., “functional”). Antibodies are primarily amino-acid based molecules but may also comprise one or more modifications (including, but not limited to the addition of sugar moieties, fluorescent moieties, chemical tags, etc.).

As used herein, “antibody-based” or “antibody-derived” compositions are monomeric or multi-meric polypeptides which comprise at least one amino-acid region derived from a known or parental antibody sequence and at least one amino acid region derived from a non-antibody sequence, e.g., mammalian protein.

Payload regions may encode polypeptides that form or function as any antibody, including antibodies that are known in the art and/or antibodies that are commercially available. The encoded antibodies may be therapeutic, diagnostic, or for research purposes. Further, polypeptides may include fragments of such antibodies or antibodies that have been developed to comprise one or more of such fragments (e.g., variable domains or complementarity determining regions (CDRs)).

In some embodiments, the viral genome of the AAV particles may comprise nucleic acids which have been engineered to enable expression of antibodies, antibody fragments, or components of any of those described in U.S. Pat. No. 7,041,807 related to YYX epitope; US20090175884, US20110305630, US20130330275 related to misfolded proteins in cancer; US20040175775 related to PrP in eye fluid; US20030114360 related to copolymers and methods of treating prion-related diseases; WO2009121176 related to insulin-induced gene peptide compositions; US20030022243, WO2003000853 related to protein aggregation assays; WO200078344 related to prion protein peptides and uses thereof. Each of these publications are incorporated by reference in their entireties.

Antibody Generation

In some embodiments, viral genomes of the AAV particles may encode antibodies or antibody-based compositions produced using methods known in the art. Such methods may include, but are not limited to, immunization and display technologies (e.g., phage display, yeast display, and ribosomal display). Antibodies may be developed, for example, using any naturally occurring or synthetic antigen. As used herein, an “antigen” is an entity which induces or evokes an immune response in an organism. An immune response is characterized by the reaction of the cells, tissues and/or organs of an organism to the presence of a foreign entity. Such an immune response typically leads to the production by the organism of one or more antibodies against the foreign entity, e.g., antigen or a portion of the antigen. As used herein, “antigens” also refer to binding partners for specific antibodies or binding agents in a display library.

In some embodiments, the sequences of the polypeptides to be encoded in the viral genomes may be derived from antibodies produced using hybridoma technology. Host animals (e.g. mice, rabbits, goats, and llamas) may be immunized by an injection with an antigenic protein to elicit lymphocytes that specifically bind to the antigen. Lymphocytes may be collected and fused with immortalized cell lines to generate hybridomas which can be cultured in a suitable culture medium to promote growth. The antibodies produced by the cultured hybridomas may be subjected to analysis to determine binding specificity of the antibodies for the target antigen. Once antibodies with desirable characteristics are identified, corresponding hybridomas may be subcloned through limiting dilution procedures and grown by standard methods. The antibodies produced by these cells may be isolated and purified using standard immunoglobulin purification procedures.

In some embodiments, the sequences of the polypeptides to be encoded in the viral genomes may be produced using heavy and light chain variable region cDNA sequences selected from hybridomas or from other sources. Sequences encoding antibody variable domains expressed by hybridomas may be determined by extracting RNA molecules from antibody-producing hybridoma cells and producing cDNA by reverse transcriptase polymerase chain reaction (PCR). PCR may be used to amplify cDNA using primers specific for heavy and light chain sequences. PCR products may then be subcloned into plasmids for sequence analysis. Antibodies may be produced by insertion of resulting variable domain sequences into expression vectors.

In some embodiments, the sequences of the polypeptides to be encoded in the viral genomes may be generated using display technologies. Display technologies used to generate polypeptides may include any of the display techniques (e.g. display library screening techniques) disclosed in International Patent Application No. WO2014074532, the contents of which are herein incorporated by reference in their entirety. In some embodiments, synthetic antibodies may be designed, selected, or optimized by screening target antigens using display technologies (e.g. phage display technologies). Phage display libraries may comprise millions to billions of phage particles, each expressing unique antibody fragments on their viral coats. Such libraries may provide richly diverse resources that may be used to select potentially hundreds of antibody fragments with diverse levels of affinity for one or more antigens of interest (McCafferty, et al., 1990. Nature. 348:552-4; Edwards, B. M. et al., 2003. JMB. 334: 103-18; Schofield, D. et al., 2007. Genome Biol. 8, R254 and Pershad, K. et al., 2010. Protein Engineering Design and Selection. 23:279-88; the contents of each of which are herein incorporated by reference in their entirety). Often, the antibody fragments present in such libraries comprise scFv antibody fragments, comprising a fusion protein of V_(H) and V_(L) antibody domains joined by a flexible linker. In some cases, scFvs may contain the same sequence with the exception of unique sequences encoding variable loops of the CDRs. In some cases, scFvs are expressed as fusion proteins, linked to viral coat proteins (e.g. the N-terminus of the viral pIII coat protein). V_(L) chains may be expressed separately for assembly with V_(H) chains in the periplasm prior to complex incorporation into viral coats. Precipitated library members may be sequenced from the bound phage to obtain cDNA encoding desired scFvs. Antibody variable domains or CDRs from such sequences may be directly incorporated into antibody sequences for recombinant antibody production or mutated and utilized for further optimization through in vitro affinity maturation.

In some embodiments, the sequences of the polypeptides to be encoded in the viral genomes may be produced using yeast surface display technology, wherein antibody variable domain sequences may be expressed on the cell surface of Saccharomyces cerevisiae. Recombinant antibodies may be developed by displaying the antibody fragment of interest as a fusion to e.g. Aga2p protein on the surface of the yeast, where the protein interacts with proteins and small molecules in a solution, scFvs with affinity toward desired receptors may be isolated from the yeast surface using magnetic separation and flow cytometry. Several cycles of yeast surface display and isolation may be done to attain scFvs with desired properties through directed evolution.

In some embodiments, the sequence of the polypeptides to be encoded in the viral genomes (e.g., antibodies) may be designed by VERSITOPE™ Antibody Generation and other methods used by BIOATLA® and described in United States Patent Publication No. US20130281303, the contents of which are herein incorporated by reference in their entirety. In brief, recombinant monoclonal antibodies are derived from B-cells of a host immuno-challenged with one or more target antigens. These methods of antibody generation do not rely on immortalized cell lines, such as hybridoma, thereby avoiding some of the associated challenges i.e., genetic instability and low production capacity, producing high affinity and high diversity recombinant monoclonal antibodies. In some embodiments, the method is a natural diversity approach. In another embodiment, the method is a high diversity approach.

In some embodiments, the sequences of the polypeptides to be encoded in the viral genomes may be generated using the BIOATLA® natural diversity approach. In the natural diversity approach of generating recombinant monoclonal antibodies described in United States Patent Publication No. US20130281303, the original pairings of variable heavy (V_(H)) and variable light (V_(L)) domains are retained from the host, yielding recombinant monoclonal antibodies that are naturally paired. These may be advantageous due to a higher likelihood of functionality as compared to non-natural pairings of V_(H) and V_(L). To produce the recombinant monoclonal antibodies, first a non-human host (i.e., rabbit, mouse, hamster, guinea pig, camel or goat) is immuno-challenged with an antigen of interest. In some embodiments, the host may be a previously challenged human patient. In other embodiments, the host may not have been immuno-challenged. B-cells are harvested from the host and screened by fluorescence activated cell sorting (FACS), or other method, to create a library of B-cells enriched in B-cells capable of binding the target antigen. The cDNA obtained from the mRNA of a single B-cell is then amplified to generate an immunoglobulin library of V_(H) and V_(L) domains. This library of immunoglobulins is then cloned into expression vectors capable of expressing the V_(H) and V_(L) domains, wherein the V_(H) and V_(L) domains remain naturally paired. The library of expression vectors is then used in an expression system to express the V_(H) and V_(L) domains in order to create an antibody library. Screening of the antibody library yields antibodies able to bind the target antigen, and these antibodies can be further characterized. Characterization may include one or more of the following: isoelectric point, thermal stability, sedimentation rate, folding rate, neutralization or antigen activity, antagonist or agonistic activity, expression level, specific and non-specific binding, inhibition of enzymatic activity, rigidity/flexibility, shape, charge, stability across pH, in solvents, under UV radiation, in mechanical stress conditions, or in sonic conditions, half-life, and glycosylation.

In some embodiments, the sequences of the polypeptides to be encoded in the viral genomes may be generated using the BIOATLA® high diversity approach. In the high diversity approach of generating recombinant monoclonal antibodies described in United States Patent Publication No. US20130281303, additional pairings of variable heavy (V_(H)) and variable light (V_(L)) domains are attained. To produce the recombinant monoclonal antibodies, B-cells harvested from the host are screened by fluorescence activated cell sorting (FACS), panning, or other method, to create a library of B-cells enriched in B-cells capable of binding the target antigen. The cDNA obtained from the mRNA of the pooled B-cells is then amplified to generate an immunoglobulin library of V_(H) and V_(L) domains. This library of immunoglobulins is then used in a biological display system (mammalian, yeast or bacterial cell surface display systems) to generate a population of cells displaying antibodies, fragments or derivatives comprising the V_(H) and V_(L) domains wherein, the antibodies, fragments or derivatives comprise V_(H) and V_(L) domain combinations that were not present in the B-cells in vivo. Screening of the cell population by FACS, with the target antigen, yields a subset of cells capable of binding the target antigen and the antibodies displayed on these cells can be further characterized. In an alternate embodiment of the high diversity approach, the immunoglobulin library comprises only V_(H) domains obtained from the B-cells of the immuno-challenged host, while the V_(L) domain(s) are obtained from another source.

In some embodiments, the sequences of the polypeptides to be encoded in the viral genomes may be evolved using BIOATLA® comprehensive approaches. The methods of generating recombinant monoclonal antibodies as described in United States Patent Publication No. US20130281303, further comprises evolving the recombinant antibody by comprehensive positional evolution (CPE™), CPE™ followed by comprehensive protein synthesis (CPS™), PCR shuffling, or other method.

In some embodiments, the sequence of the polypeptides to be encoded in the viral genomes (e.g., antibodies) may be derived from any of the BIOATLA® protein evolution methods described in International Publication WO2012009026, the contents of which are herein incorporated by reference in their entirety. In this method, mutations are systematically performed throughout the polypeptide or molecule of interest, a map is created providing useful informatics to guide the subsequent evolutionary steps. Not wishing to be bound by theory, these evolutionary methods typically start with a template polypeptide and a mutant is derived therefrom, which has desirable properties or characteristics. Non-limiting examples of evolutionary techniques include polymerase chain reaction (PCR), error prone PCR, oligonucleotide-directed mutagenesis, cassette mutagenesis, shuffling, assembly PCR, sexual PCR mutagenesis, in vivo mutagenesis, site-specific mutagenesis, gene reassembly, gene site saturated mutagenesis, in vitro mutagenesis, ligase chain reaction, oligonucleotide synthesis or any combination thereof.

In some embodiments, the BIOATLA® evolution method is Comprehensive Positional Evolution (CPE™). In CPE, naturally occurring amino acid variants are generated for each of the codons of the template polypeptide, wherein 63 different codon options exist for each amino acid variant. A set of polypeptides with single amino acid mutations are generated and the mutations are then confirmed by sequencing or other method known in the art and each amino acid change screened for improved function, neutral mutations, inhibitory mutations, expression, and compatibility with the host system. An EvoMap™ is created that describes in detail the effects of each amino acid mutation on the properties and characteristics of that polypeptide. The data from the EvoMap™ may be utilized to produce polypeptides with more than one amino acid mutation, wherein the resultant multi-site mutant polypeptides can be screened for desirable characteristics.

In some embodiments, the BIOATLA® evolution method is Synergy Evolution, wherein an EvoMap™ is used to identify amino acid positions to introduce 2-20 mutations simultaneously to produce a combinatorial effect. The resulting multi-site mutant polypeptides may be screened on one or more pre-determined characteristics to identify “upmutants” wherein the function of the mutant is improved as compared to the parent polypeptide. In some embodiments, Synergy Evolution is used to enhance binding affinity of an antibody.

In some embodiments, the BIOATLA® evolution method is Flex Evolution, wherein an EvoMap™ is used to identify fully mutable sites within a polypeptide that may then be targeted for alteration, such as introduction of glycosylation sites or chemical conjugation.

In some embodiments, the BIOATLA® evolution method is Comprehensive Positional Insertion Evolution (CPI™), wherein an amino acid is inserted after each amino acid of a template polypeptide to generate a set of lengthened polypeptides. CPI may be used to insert 1, 2, 3, 4, or 5 amino acids at each new position. The resultant lengthened polypeptides are sequenced and assayed for one or more pre-determined properties and evaluated in comparison to its template or parent molecule. In some embodiments, the binding affinity and immunogenicity of the resultant polypeptides are assayed. In some embodiments, the lengthened polypeptides are further mutated and mapped to identify polypeptides with desirable characteristics.

In some embodiments, the BIOATLA® evolution approach is Comprehensive Positional Deletion Evolution (CPD™), wherein each amino acid of the template polypeptide is individually and systematically deleted one at a time. The resultant shortened polypeptides are then sequenced and evaluated by assay for at least one pre-determined feature. In some embodiments, the shortened polypeptides are further mutated and mapped to identify polypeptides with desirable characteristics.

In some embodiments, the BIOATLA® evolution approach is Combinatorial Protein Synthesis (CPS™), wherein mutants identified in CPE, CPI, CPD, or other evolutionary techniques are combined for polypeptide synthesis. These combined mutant polypeptides are then screened for enhanced properties and characteristics. In some embodiments CPS is combined with any of the aforementioned evolutionary or polypeptide synthesis methods.

In some embodiments, the sequence of the polypeptides to be encoded in the viral genomes (e.g., antibodies) may be derived from the BIOATLA®, Comprehensive Integrated Antibody Optimization (CIAO!™) described in U.S. Pat. No. 8,859,467, the contents of which are herein incorporated by reference in their entirety. The CIAO!™ method allows for simultaneous evolution of polypeptide performance and expression optimization, within a eukaryotic cell host (i.e., mammalian or yeast cell host). First, an antibody library is generated in a mammalian cell production host by antibody cell surface display, wherein the generated antibody library targets a particular antigen of interest. The antibody library is then screened by any method known in the art, for one or more properties or characteristics. One or more antibodies of the library, with desirable properties or characteristics are chosen for further polypeptide evolution by any of the methods known in the art, to produce a library of mutant antibodies by antibody cell surface display in a mammalian cell production host. The generated mutant antibodies are screened for one or more predetermined properties or characteristics, whereby an upmutant is selected, wherein the upmutant has enhanced or improved characteristics as compared to the parent template polypeptide.

In some embodiments, the sequences of the polypeptides to be encoded in the viral genomes may be humanized by the methods of BIOATLA® as described in United States Patent Publication US20130303399, the contents of which are herein incorporated by reference in their entirety. In this method, for generating enhanced full-length humanized antibodies in mammalian cells, no back-mutations are required to retain affinity to the antigen and no CDR grafting or phage-display is necessary. The generated humanized antibody has reduced immunogenicity and equal or greater affinity for the target antigen as compared to the parent antibody. The variable regions or CDRs of the generated humanized antibody are derived from the parent or template, whereas the framework and constant regions are derived from one or more human antibodies. To start, the parent, or template antibody is selected, cloned and each CDR sequence identified and synthesized into a CDR fragment library. Double stranded DNA fragment libraries for V_(H) and V_(L) are synthesized from the CDR fragment encoding libraries, wherein at least one CDR fragment library is derived from the template antibody and framework (FW) fragment encoding libraries, wherein the FW fragment library is derived from a pool of human frameworks obtained from natively expressed and functional human antibodies. Stepwise liquid phase ligation of FW and CDR encoding fragments is then used to generate both V_(H) and V_(L) fragment libraries. The V_(H) and V_(L) fragment libraries are then cloned into expression vectors to create a humanization library, which is further transfected into cells for expression of full length humanized antibodies and used to create a humanized antibody library. The humanized antibody library is then screened to determine expression level of the humanized antibodies, affinity or binding ability for the antigen, and additional improved or enhanced characteristics, as compared to the template or parent antibody. Non-limiting examples of characteristics that may be screened include equilibrium dissociation constant (K_(D)), stability, melting temperature (T_(m)), pI, solubility, expression level, reduced immunogenicity, and improved effector function.

In some embodiments, the sequences of the polypeptides to be encoded in the viral genomes may be generated by the BIOATLA® method for preparing conditionally active antibodies as described in International Publications WO2016033331 and WO2016036916, the contents of which are herein incorporated by reference in their entirety. As used herein, the term “conditionally active” refers to a molecule that is active at an aberrant condition. Further, the conditionally active molecule may be virtually inactive at normal physiological conditions. Aberrant conditions may result from changes in pH, temperature, osmotic pressure, osmolality, oxidative stress, electrolyte concentration, and/or chemical or proteolytic resistance, as non-limiting examples.

The method of preparing a conditionally active antibody is described in International Publications WO2016033331 and WO2016036916 and summarized herein. Briefly, a wild-type polypeptide is selected and the DNA is evolved to create mutant DNAs. Non-limiting examples of evolutionary techniques that may be used to evolve the DNA include polymerase chain reaction (PCR), error prone PCR, shuffling, oligonucleotide-directed mutagenesis, assembly PCR, sexual PCR mutagenesis, in vivo mutagenesis, site-specific mutagenesis, gene reassembly, gene site saturated mutagenesis, in vitro mutagenesis, ligase chain reaction, oligonucleotide synthesis or any combination thereof. Once mutant DNAs are created, they are expressed in a eukaryotic cell production host (i.e., fungal, insect, mammalian, adenoviral, plant), wherein a mutant polypeptide is produced. The mutant polypeptide and the corresponding wild-type polypeptide are then subjected to assays under both normal physiological conditions and aberrant conditions in order to identify mutants that exhibit a decrease in activity in the assay at normal physiological conditions as compared to the wild-type polypeptide and/or an increase in activity in the assay under aberrant conditions, as compared to the corresponding wild-type polypeptide. The desired conditionally active mutant may then be produced in the aforementioned eukaryotic cell production host.

In some embodiments, the conditionally active antibody is a “mirac protein” as described by BIOATLA® in U.S. Pat. No. 8,709,755, the contents of which are herein incorporated by reference in their entirety. As used herein “mirac protein” refers to a conditionally active antibody that is virtually inactive at body temperature but active at lower temperatures.

In some embodiments, the sequence of the polypeptides to be encoded in the viral genomes (e.g., antibodies) may be derived based on any of the BIOATLA® methods including, but not limited to, VERSITOPE™ Antibody Generation, natural diversity approaches, and high diversity approaches for generating monoclonal antibodies, methods for generation of conditionally active polypeptides, humanized antibodies, mirac proteins, multi-specific antibodies or cross-species active mutant polypeptides, Comprehensive Integrated Antibody Optimization (CIAO!™), Comprehensive Positional Evolution (CPE™), Synergy Evolution, Flex Evolution, Comprehensive Positional Insertion Evolution (CPI™), Comprehensive Positional Deletion Evolution (CPD™), Combinatorial Protein Synthesis (CPS™), or any combination thereof. These methods are described in U.S. Pat. Nos. 8,859,467 and 8,709,755 and United States Publication Nos. US20130281303, US20130303399, US20150065690, US20150252119, US20150086562 and US20100138945, and International Publication Nos. WO2015105888, WO2012009026, WO2011109726, WO2016036916, and WO2016033331, the contents of each of which are herein incorporated by reference in their entirety.

In some embodiments, antibodies of the present disclosure are generated by any of the aforementioned means to target one or more of the following epitopes of the tau protein; phosphorylated tau peptides, pS396, pS396-pS404, pS404, pS396-pS404-pS422, pS422, pS199, pS199-pS202, pS202, pT181, pT231, cis-pT231, any of the following acetylated sites acK174, acK274, acK280, acK281 and/or any combination thereof

Antibody Fragments and Variants

In some embodiments, antibody fragments encoded by payloads comprise antigen binding regions from intact antibodies. Examples of antibody fragments may include, but are not limited to Fab, Fab′, F(ab′)₂, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules; and multispecific antibodies formed from antibody fragments. Papain digestion of antibodies produces two identical antigen-binding fragments, called “Fab” fragments, each with a single antigen-binding site. Also produced is a residual “Fc” fragment, whose name reflects its ability to crystallize readily. Pepsin treatment yields an F(ab)₂ fragment that has two antigen-binding sites and is still capable of cross-linking antigen. Compounds and/or compositions of the present disclosure may comprise one or more of these fragments. For the purposes herein, an “antibody” may comprise a heavy and light variable domain as well as an Fe region.

In some embodiments, the Fc region may be a modified Fc region, as described in US Patent Publication US20150065690, wherein the Fc region may have a single amino acid substitution as compared to the corresponding sequence for the wild-type Fc region, wherein the single amino acid substitution yields an Fc region with preferred properties to those of the wild-type Fc region. Non-limiting examples of Fc properties that may be altered by the single amino acid substitution include bind properties or response to pH conditions

As used herein, the term “native antibody” refers to a usually heterotetrameric glycoprotein of about 150,000 Daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Genes encoding antibody heavy and light chains are known and segments making up each have been well characterized and described (Matsuda, F. et al., 1998. The Journal of Experimental Medicine. 188(11): 2151-62 and Li, A. et al., 2004. Blood. 103 (12: 4602-9, the content of each of which are herein incorporated by reference in their entirety). Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain (V_(H)) followed by a number of constant domains. Each light chain has a variable domain at one end (V_(L)) and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain.

As used herein, the term “variable domain” refers to specific antibody domains found on both the antibody heavy and light chains that differ extensively in sequence among antibodies and are used in the binding and specificity of each particular antibody for its particular antigen. Variable domains comprise hypervariable regions. As used herein, the term “hypervariable region” refers to a region within a variable domain comprising amino acid residues responsible for antigen binding. The amino acids present within the hypervariable regions determine the structure of the complementarity determining regions (CDRs) that become part of the antigen-binding site of the antibody. As used herein, the term “CDR” refers to a region of an antibody comprising a structure that is complimentary to its target antigen or epitope. Other portions of the variable domain, not interacting with the antigen, are referred to as framework (FW) regions. The antigen-binding site (also known as the antigen combining site or paratope) comprises the amino acid residues necessary to interact with a particular antigen. The exact residues making up the antigen-binding site are typically elucidated by co-crystallography with bound antigen, however computational assessments can also be used based on comparisons with other antibodies (Strohl, W. R. Therapeutic Antibody Engineering. Woodhead Publishing, Philadelphia Pa. 2012. Ch. 3, p 47-54, the contents of which are herein incorporated by reference in their entirety). Determining residues making up CDRs may include the use of numbering schemes including, but not limited to, those taught by Kabat [Wu, T. T. et al., 1970, JEM, 132(2):211-50 and Johnson, G. et al., 2000, Nucleic Acids Res. 28(1): 214-8, the contents of each of which are herein incorporated by reference in their entirety], Chothia [Chothia and Lesk, J. Mol. Biol. 196, 901 (1987), Chothia et al., Nature 342, 877 (1989) and Al-Lazikani, B. et al., 1997, J. Mol. Biol. 273(4):927-48, the contents of each of which are herein incorporated by reference in their entirety], Lefranc (Lefranc, M. P. et al., 2005, Immunome Res. 1:3) and Honegger (Honegger, A. and Pluckthun, A. 2001. J. Mol. Biol. 309(3):657-70, the contents of which are herein incorporated by reference in their entirety).

V_(H) and V_(L) domains have three CDRs each. VL CDRs are referred to herein as CDR-L1, CDR-L2 and CDR-L3, in order of occurrence when moving from N- to C-terminus along the variable domain polypeptide. VH CDRs are referred to herein as CDR-H1, CDR-H2, and CDR-H3, in order of occurrence when moving from N- to C-terminus along the variable domain polypeptide. Each of CDRs have favored canonical structures with the exception of the CDR-H3, which comprises amino acid sequences that may be highly variable in sequence and length between antibodies resulting in a variety of three-dimensional structures in antigen-binding domains (Nikoloudis, D. et al., 2014. Peer J. 2:e456; the contents of which are herein incorporated by reference in their entirety). In some cases. CDR-H3s may be analyzed among a panel of related antibodies to assess antibody diversity. Various methods of determining CDR sequences are known in the art and may be applied to known antibody sequences (Strohl, W. R. Therapeutic Antibody Engineering. Woodhead Publishing, Philadelphia Pa. 2012. Ch. 3, p 47-54, the contents of which are herein incorporated by reference in their entirety).

As used herein, the term “Fv” refers to an antibody fragment comprising the minimum fragment on an antibody needed to form a complete antigen-binding site. These regions consist of a dimer of one heavy chain and one light chain variable domain in tight, non-covalent association. Fv fragments can be generated by proteolytic cleavage but are largely unstable. Recombinant methods are known in the art for generating stable Fv fragments, typically through insertion of a flexible linker between the light chain variable domain and the heavy chain variable domain [to form a single chain Fv (scFv)] or through the introduction of a disulfide bridge between heavy and light chain variable domains (Strohl, W. R. Therapeutic Antibody Engineering. Woodhead Publishing, Philadelphia Pa. 2012. Ch. 3, p 46-47, the contents of which are herein incorporated by reference in their entirety).

As used herein, the term “light chain” refers to a component of an antibody from any vertebrate species assigned to one of two clearly distinct types, called kappa and lambda based on amino acid sequences of constant domains. Depending on the amino acid sequence of the constant domain of their heavy chains, antibodies can be assigned to different classes. There are five major classes of intact antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA, and IgA2.

As used herein, the term “single chain Fv” or “scFv” refers to a fusion protein of V_(H) and V_(L) antibody domains, wherein these domains are linked together into a single polypeptide chain by a flexible peptide linker. In some embodiments, the Fv polypeptide linker enables the scFv to form the desired structure for antigen binding. In some embodiments, scFvs are utilized in conjunction with phage display, yeast display or other display methods where they may be expressed in association with a surface member (e.g. phage coat protein) and used in the identification of high affinity peptides for a given antigen.

As used herein, the term “bispecific antibody” refers to an antibody capable of binding two different antigens. Such antibodies typically comprise regions from at least two different antibodies. Bispecific antibodies may include any of those described in Riethmuller, G. 2012. Cancer Immunity. 12:12-18, Marvin, J. S. et al., 2005. Acta Pharmacologica Sinica. 26(6):649-58 and Schaefer, W. et al., 2011. PNAS. 108(27):11187-92, the contents of each of which are herein incorporated by reference in their entirety.

As used herein, the term “diabody” refers to a small antibody fragment with two antigen-binding sites. Diabodies comprise a heavy chain variable domain V_(H) connected to a light chain variable domain V_(L) in the same polypeptide chain. By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites. Diabodies are described more fully in, for example, EP 404097; WO 9311161; and Hollinger et al. (Hollinger, P. et al., “Diabodies”: Small bivalent and bispecific antibody fragments. PNAS. 1993. 90:6444-8) the contents of each of which are incorporated herein by reference in their entirety.

The term “intrabody” refers to a form of antibody that is not secreted from a cell in which it is produced, but instead targets one or more intracellular proteins. Intrabodies may be used to affect a multitude of cellular processes including, but not limited to intracellular trafficking, transcription, translation, metabolic processes, proliferative signaling, and cell division. In some embodiments, methods of the present disclosure may include intrabody-based therapies. In some such embodiments, variable domain sequences and/or CDR sequences disclosed herein may be incorporated into one or more constructs for intrabody-based therapy.

As used herein, the term “monoclonal antibody” refers to an antibody obtained from a population of substantially homogeneous cells (or clones), i.e., the individual antibodies comprising the population are identical and/or bind the same epitope, except for possible variants that may arise during production of the monoclonal antibodies, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen

The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and is not to be construed as requiring production of the antibody by any particular method. The monoclonal antibodies herein include “chimeric” antibodies (immunoglobulins) in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies.

As used herein, the term “humanized antibody” refers to a chimeric antibody comprising a minimal portion from one or more non-human (e.g., murine) antibody source(s) with the remainder derived from one or more human immunoglobulin sources. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from the hypervariable region from an antibody of the recipient are replaced by residues from the hypervariable region from an antibody of a non-human species (donor antibody) such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity, and/or capacity.

In some embodiments, viral genomes of the present disclosure may encode antibody mimetics. As used herein, the term “antibody mimetic” refers to any molecule which mimics the function or effect of an antibody and which binds specifically and with high affinity to their molecular targets. In some embodiments, antibody mimetics may be monobodies, designed to incorporate the fibronectin type III domain (Fn3) as a protein scaffold (U.S. Pat. Nos. 6,673,901; 6,348,584). In some embodiments, antibody mimetics may be those known in the art including, but are not limited to affibody molecules, affilins, affitins, anticalins, avimers, Centyrins, DARPINS™, fynomers, Kunitz domains, and domain peptides. In other embodiments, antibody mimetics may include one or more non-peptide regions.

As used herein, the term “antibody variant” refers to a modified antibody (in relation to a native or starting antibody) or a biomolecule resembling a native or starting antibody in structure and/or function (e.g., an antibody mimetic). Antibody variants may be altered in their amino acid sequence, composition, or structure as compared to a native antibody. Antibody variants may include, but are not limited to, antibodies with altered isotypes (e.g., IgA, IgD, IgE, IgG1, IgG2, IgG3, IgG4, or IgM), humanized variants, optimized variants, multispecific antibody variants (e.g., bispecific variants), and antibody fragments.

The preparation of antibodies, whether monoclonal or polyclonal, is known in the art. Techniques for the production of antibodies are well known in the art and described, e.g. in Harlow and Lane “Antibodies, A Laboratory Manual”, Cold Spring Harbor Laboratory Press, 1988; Harlow and Lane “Using Antibodies: A Laboratory Manual” Cold Spring Harbor Laboratory Press, 1999 and “Therapeutic Antibody Engineering: Current and Future Advances Driving the Strongest Growth Area in the Pharmaceutical Industry” Woodhead Publishing, 2012.

Multispecific Antibodies

In some embodiments, payloads may encode antibodies that bind more than one epitope. As used herein, the terms “multibody” or “multispecific antibody” refer to an antibody wherein two or more variable regions bind to different epitopes. The epitopes may be on the same or different targets. In certain embodiments, a multi-specific antibody is a “bispecific antibody,” which recognizes two different epitopes on the same or different antigens.

In some embodiments, multi-specific antibodies may be prepared by the methods used by BIOATLA® and described in International Patent publication WO201109726, the contents of which are herein incorporated by reference in their entirety. First a library of homologous, naturally occurring antibodies is generated by any method known in the art (i.e., mammalian cell surface display), then screened by FACSAria or another screening method, for multi-specific antibodies that specifically bind to two or more target antigens. In some embodiments, the identified multi-specific antibodies are further evolved by any method known in the art, to produce a set of modified multi-specific antibodies. These modified multi-specific antibodies are screened for binding to the target antigens. In some embodiments, the multi-specific antibody may be further optimized by screening the evolved modified multi-specific antibodies for optimized or desired characteristics.

In some embodiments, multi-specific antibodies may be prepared by the methods used by BIOATLA® and described in Unites States Publication No. US20150252119, the contents of which are herein incorporated by reference in their entirety. In one approach, the variable domains of two parent antibodies, wherein the parent antibodies are monoclonal antibodies are evolved using any method known in the art in a manner that allows a single light chain to functionally complement heavy chains of two different parent antibodies. Another approach requires evolving the heavy chain of a single parent antibody to recognize a second target antigen. A third approach involves evolving the light chain of a parent antibody so as to recognize a second target antigen. Methods for polypeptide evolution are described in International Publication WO2012009026, the contents of which are herein incorporated by reference in their entirety, and include as non-limiting examples, Comprehensive Positional Evolution (CPE), Combinatorial Protein Synthesis (CPS), Comprehensive Positional Insertion (CPI), Comprehensive Positional Deletion (CPD), or any combination thereof. The Fc region of the multi-specific antibodies described in United States Publication No. US20150252119 may be created using a knob-in-hole approach, or any other method that allows the Fc domain to form heterodimers. The resultant multi-specific antibodies may be further evolved for improved characteristics or properties such as binding affinity for the target antigen.

Bispecific Antibodies

In some embodiments, payloads may encode bispecific antibodies. Bispecific antibodies are capable of binding two different antigens. Such antibodies typically comprise antigen-binding regions from at least two different antibodies. For example, a bispecific monoclonal antibody (BsMAb, BsAb) is an artificial protein composed of fragments of two different monoclonal antibodies, thus allowing the BsAb to bind to two different types of antigen.

In some cases, payloads encode bispecific antibodies comprising antigen-binding regions from two different anti-tau antibodies. For example, such bispecific antibodies may comprise binding regions from two different antibodies selected from Table 3.

Bispecific antibody frameworks may include any of those described in Riethmuller, G., 2012. Cancer Immunity. 12:12-18; Marvin, J. S. et al., 2005. Acta Pharmacologica Sinica. 26(6):649-58; and Schaefer, W. et al., 2011. PNAS. 108(27):11187-92, the contents of each of which are herein incorporated by reference in their entirety.

New generations of BsMAb, called “trifunctional bispecific” antibodies, have been developed. These consist of two heavy and two light chains, one each from two different antibodies, where the two Fab regions (the arms) are directed against two antigens, and the Fc region (the foot) comprises the two heavy chains and forms the third binding site.

Of the two paratopes that form the tops of the variable domains of a bispecific antibody, one can be directed against a target antigen and the other against a T-lymphocyte antigen like CD3. In the case of trifunctional antibodies, the Fc region may additionally bind to a cell that expresses Fe receptors, like a macrophage, a natural killer (NK) cell or a dendritic cell. In sum, the targeted cell is connected to one or two cells of the immune system, which subsequently destroy it.

Other types of bispecific antibodies have been designed to overcome certain problems, such as short half-life, immunogenicity and side-effects caused by cytokine liberation. They include chemically linked Fabs, consisting only of the Fab regions, and various types of bivalent and trivalent single-chain variable fragments (scFvs), fusion proteins mimicking the variable domains of two antibodies. The furthest developed of these newer formats are the bi-specific T-cell engagers (BiTEs) and mAb2's, antibodies engineered to contain an Fcab antigen-binding fragment instead of the Fc constant region.

Using molecular genetics, two scFvs can be engineered in tandem into a single polypeptide, separated by a linker domain, called a “tandem scFv” (tascFv). TascFvs have been found to be poorly soluble and require refolding when produced in bacteria, or they may be manufactured in mammalian cell culture systems, which avoids refolding requirements but may result in poor yields. Construction of a tascFv with genes for two different scFvs yields a “bispecific single-chain variable fragments” (bis-scFvs). Only two tascFvs have been developed clinically by commercial firms; both are bispecific agents in active early phase development by Micromet for oncologic indications and are described as “Bispecific T-cell Engagers (BiTE).” Blinatumomab is an anti-CD19/anti-CD3 bispecific tascFv that potentiates T-cell responses to B-cell non-Hodgkin lymphoma in Phase 2. MT110 is an anti-EP-CAM/anti-CD3 bispecific tascFv that potentiates T-cell responses to solid tumors in Phase 1. Bispecific, tetravalent “TandAbs” are also being researched by Affimed (Nelson, A. L., MAbs. 2010. January-February; 2(1):77-83).

In some embodiments, payloads may encode antibodies comprising a single antigen-binding domain. These molecules are extremely small, with molecular weights approximately one-tenth of those observed for full-sized mAbs. Further antibodies may include “nanobodies” derived from the antigen-binding variable heavy chain regions (V_(HH)s) of heavy chain antibodies found in camels and llamas, which lack light chains (Nelson, A. L., MAbs. 2010. January-February; 2(1):77-83).

Disclosed and claimed in PCT Publication WO2014144573 to Memorial Sloan-Kettering Cancer Center are multimerization technologies for making dimeric multispecific binding agents (e.g., fusion proteins comprising antibody components) with improved properties over multispecific binding agents without the capability of dimerization.

In some cases, payloads may encode tetravalent bispecific antibodies (TetBiAbs as disclosed and claimed in PCT Publication WO2014144357). TetBiAbs feature a second pair of Fab fragments with a second antigen specificity attached to the C-terminus of an antibody, thus providing a molecule that is bivalent for each of the two antigen specificities. The tetravalent antibody is produced by genetic engineering methods, by linking an antibody heavy chain covalently to a Fab light chain, which associates with its cognate, co-expressed Fab heavy chain.

In some aspects, payloads may encode biosynthetic antibodies as described in U.S. Pat. No. 5,091,513, the contents of which are herein incorporated by reference in their entirety. Such antibody may include one or more sequences of amino acids constituting a region which behaves as a biosynthetic antibody binding site (BABS). The sites comprise 1) non-covalently associated or disulfide bonded synthetic V_(H) and V_(L) dimers, 2) V_(H)-V_(L) or V_(L)-V_(H) single chains wherein the V_(H) and V_(L) are attached by a polypeptide linker, or 3) individuals V_(H) or V_(L) domains. The binding domains comprise linked CDR and FR regions, which may be derived from separate immunoglobulins. The biosynthetic antibodies may also include other polypeptide sequences which function, e.g., as an enzyme, toxin, binding site, or site of attachment to an immobilization media or radioactive atom. Methods are disclosed for producing the biosynthetic antibodies, for designing BABS having any specificity that can be elicited by in vivo generation of antibody, and for producing analogs thereof.

In some embodiments, payloads may encode antibodies with antibody acceptor frameworks taught in U.S. Pat. No. 8,399,625. Such antibody acceptor frameworks may be particularly well suited accepting CDRs from an antibody of interest. In some cases, CDRs from anti-tau antibodies known in the art or developed according to the methods presented herein may be used.

Miniaturized Antibody

In some embodiments, the antibody encoded by the payloads may be a “miniaturized” antibody. Among the best examples of mAb miniaturization are the small modular immunopharmaceuticals (SMIPs) from Trubion Pharmaceuticals. These molecules, which can be monovalent or bivalent, are recombinant single-chain molecules containing one V_(L), one V_(H) antigen-binding domain, and one or two constant “effector” domains, all connected by linker domains. Presumably, such a molecule might offer the advantages of increased tissue or tumor penetration claimed by fragments while retaining the immune effector functions conferred by constant domains. At least three “miniaturized” SMIPs have entered clinical development. TRU-015, an anti-CD20 SMIP developed in collaboration with Wyeth, is the most advanced project, having progressed to Phase 2 for rheumatoid arthritis (RA). Earlier attempts in systemic lupus erythrematosus (SLE) and B cell lymphomas were ultimately discontinued. Trubion and Facet Biotechnology are collaborating in the development of TRU-016, an anti-CD37 SMIP, for the treatment of CLL and other lymphoid neoplasias, a project that has reached Phase 2. Wyeth has licensed the anti-CD20 SMIP SBI-087 for the treatment of autoimmune diseases, including RA, SLE, and possibly multiple sclerosis, although these projects remain in the earliest stages of clinical testing. (Nelson, A. L., MAbs. 2010. January-February; 2(1):77-83).

Diabodies

In some embodiments, payloads may encode diabodies. Diabodies are functional bispecific single-chain antibodies (bscAb). These bivalent antigen-binding molecules are composed of non-covalent dimers of scFvs, and can be produced in mammalian cells using recombinant methods. (See, e.g., Mack et al. Proc. Natl. Acad. Si., 92: 7021-7025, 1995). Few diabodies have entered clinical development. An iodine-123-labeled diabody version of the anti-CEA chimeric antibody cT84.66 has been evaluated for pre-surgical immunoscintigraphic detection of colorectal cancer in a study sponsored by the Beckman Research Institute of the City of Hope (Clinicaltrials.gov NCT00647153) (Nelson, A. L., MAbs., 2010. January-February; 2(1):77-83).

Unibody

In some embodiments, payloads may encode a “unibody,” in which the hinge region has been removed from IgG4 molecules. While IgG4 molecules are unstable and can exchange light-heavy chain heterodimers with one another, deletion of the hinge region prevents heavy chain-heavy chain pairing entirely, leaving highly specific monovalent light/heavy heterodimers, while retaining the Fc region to ensure stability and half-life in vivo. This configuration may minimize the risk of immune activation or oncogenic growth, as IgG4 interacts poorly with FcRs and monovalent unibodies fail to promote intracellular signaling complex formation. These contentions are, however, largely supported by laboratory, rather than clinical, evidence. Other antibodies may be “miniaturized” antibodies, which are compacted 100 kDa antibodies (see, e.g., Nelson. A. L., MAbs., 2010. January-February; 2(1):77-83).

Intrabodies

In some embodiments, payloads may encode intrabodies. Intrabodies are a form of antibody that is not secreted from a cell in which it is produced, but instead targets one or more intracellular proteins. Intrabodies are expressed and function intracellularly, and may be used to affect a multitude of cellular processes including, but not limited to intracellular trafficking, transcription, translation, metabolic processes, proliferative signaling and cell division. In some embodiments, methods described herein include intrabody-based therapies. In some such embodiments, variable domain sequences and/or CDR sequences disclosed herein are incorporated into one or more constructs for intrabody-based therapy. For example, intrabodies may target one or more glycated intracellular proteins or may modulate the interaction between one or more glycated intracellular proteins and an alternative protein.

More than two decades ago, intracellular antibodies against intracellular targets were first described (Biocca, Neuberger and Cattaneo EMBO J. 9: 101-108, 1990). The intracellular expression of intrabodies in different compartments of mammalian cells allows blocking or modulation of the function of endogenous molecules (Biocca, et al., EMBO J. 9: 101-108, 1990; Colby et al., Proc. Natl. Acad. Sci. U.S.A. 101: 17616-21, 2004). Intrabodies can alter protein folding, protein-protein, protein-DNA, protein-RNA interactions and protein modification. They can induce a phenotypic knockout and work as neutralizing agents by direct binding to the target antigen, by diverting its intracellular trafficking or by inhibiting its association with binding partners. They have been largely employed as research tools and are emerging as therapeutic molecules for the treatment of human diseases such as viral pathologies, cancer and misfolding diseases. The fast-growing bio-market of recombinant antibodies provides intrabodies with enhanced binding specificity, stability, and solubility, together with lower immunogenicity, for their use in therapy (Biocca, abstract in Antibody Expression and Production Cell Engineering Volume 7, 2011, pp. 179-195).

In some embodiments, intrabodies have advantages over interfering RNA (iRNA); for example, iRNA has been shown to exert multiple non-specific effects, whereas intrabodies have been shown to have high specificity and affinity to target antigens. Furthermore, as proteins, intrabodies possess a much longer active half-life than iRNA. Thus, when the active half-life of the intracellular target molecule is long, gene silencing through iRNA may be slow to yield an effect, whereas the effects of intrabody expression can be almost instantaneous. Lastly, it is possible to design intrabodies to block certain binding interactions of a particular target molecule, while sparing others.

Intrabodies are often single chain variable fragments (scFvs) expressed from a recombinant nucleic acid molecule and engineered to be retained intracellularly (e.g., retained in the cytoplasm, endoplasmic reticulum, or periplasm). Intrabodies may be used, for example, to ablate the function of a protein to which the intrabody binds. The expression of intrabodies may also be regulated through the use of inducible promoters in the nucleic acid expression vector comprising the intrabody. Intrabodies may be produced for use in the viral genomes using methods known in the art, such as those disclosed and reviewed in: (Marasco et al., 1993 Proc. Natl. Acad. Sci. USA, 90: 7889-7893; Chen et al., 1994, Hum. Gene her. 5:595-601; Chen et al., 1994, Proc. Natl. Acad. Sci. USA, 91: 5932-5936; Maciejewski et al., 1995, Nature Med., 1: 667-673; Marasco, 1995, Immunotech, 1: 1-19; Mhashilkar, et al., 1995, EMBO J. 14: 1542-51; Chen et al., 1996, Hum. Gene Therap., 7: 1515-1525; Marasco, Gene Ther. 4:11-15, 1997; Rondon and Marasco, 1997, Annu. Rev. Microbiol. 51:257-283; Cohen, et al., 1998, Oncogene 17:2445-56; Proba et al., 1998, J. Mol. Biol. 275:245-253; Cohen et al., 1998, Oncogene 17:2445-2456; Hassanzadeh, et al., 1998. FEBS Lett. 437:81-6; Richardson et al., 1998. Gene Ther. 5:635-44; Ohage and Steipe, 1999, J. Mol. Biol. 291:1119-1128; Ohage et al., 1999, J. Mol. Biol. 291:1129-1134; Wirtz and Steipe, 1999, Protein Sci. 8:2245-2250; Zhu et al., 1999, J. Immunol. Methods 231:207-222; Arafat et al., 2000, Cancer Gene Ther. 7:1250-6; der Maur et al., 2002, J. Biol. Chem. 277:45075-85; Mhashilkar et al., 2002, Gene Ther. 9:307-19; and Wheeler et al., 2003, FASEB J. 17: 1733-5; and references cited therein). In particular, a CCR5 intrabody has been produced by Steinberger el al., 2000, Proc. Natl. Acad. Sci. USA 97:805-810). See generally Marasco, W A, 1998, “Intrabodies: Basic Research and Clinical Gene Therapy Applications” Springer: New York; and for a review of scFvs, see Pluckthun in “The Pharmacology of Monoclonal Antibodies,” 1994, vol. 113, Rosenburg and Moore eds. Springer-Verlag, New York, pp. 269-315.

Sequences from donor antibodies may be used to develop intrabodies. Intrabodies are often recombinantly expressed as single domain fragments such as isolated V_(H) and VL domains or as a single chain variable fragment (scFv) antibody within the cell. For example, intrabodies are often expressed as a single polypeptide to form a single chain antibody comprising the variable domains of the heavy and light chains joined by a flexible linker polypeptide. Intrabodies typically lack disulfide bonds and are capable of modulating the expression or activity of target genes through their specific binding activity. Single chain antibodies can also be expressed as a single chain variable region fragment joined to the light chain constant region.

As is known in the art, an intrabody can be engineered into recombinant polynucleotide vectors to encode sub-cellular trafficking signals at its N or C terminus to allow expression at high concentrations in the sub-cellular compartments where a target protein is located. For example, intrabodies targeted to the endoplasmic reticulum (ER) are engineered to incorporate a leader peptide and, optionally, a C-terminal ER retention signal, such as the KDEL amino acid motif (SEQ ID NO: 4545). Intrabodies intended to exert activity in the nucleus are engineered to include a nuclear localization signal. Lipid moieties are joined to intrabodies in order to tether the intrabody to the cytosolic side of the plasma membrane. Intrabodies can also be targeted to exert function in the cytosol. For example, cytosolic intrabodies are used to sequester factors within the cytosol, thereby preventing them from being transported to their natural cellular destination.

There are certain technical challenges with intrabody expression. In particular, protein conformational folding and structural stability of the newly synthesized intrabody within the cell is affected by reducing conditions of the intracellular environment.

Intrabodies may be promising therapeutic agents for the treatment of misfolding diseases, including Tauopathies, prion diseases, Alzheimer's, Parkinson's, and Huntington's, because of their virtually infinite ability to specifically recognize the different conformations of a protein, including pathological isoforms, and because they can be targeted to the potential sites of aggregation (both intra- and extracellular sites). These molecules can work as neutralizing agents against amyloidogenic proteins by preventing their aggregation, and/or as molecular shunters of intracellular traffic by rerouting the protein from its potential aggregation site (Cardinale, and Biocca, Curr. Mol. Med. 2008, 8:2-11).

Maxibodies

In some embodiments, the payloads encode a maxibody (bivalent scFv fused to the amino terminus of the Fc (CH2-CH3 domains) of IgG.

Chimeric Antigen Receptors

In some embodiments, the polypeptides encoded by the viral genomes (e.g., antibodies) may be used to generate chimeric antigen receptors (CARs) as described by BIOATLA® in International Publications WO2016033331 and WO2016036916, the contents of which are herein incorporated by reference in their entirety. As used herein, a “chimeric antigen receptor (CAR)” refers to an artificial chimeric protein comprising at least one antigen specific targeting region (ASTR), wherein the antigen specific targeting region comprises a full-length antibody or a fragment thereof that specifically binds to a target antigen. The ASTR may comprise any of the following: a full length heavy or light chain, an Fab fragment, a single chain Fv fragment, a divalent single chain antibody, or a diabody. As a non-limiting example, the ASTR of a CAR may be any of the antibodies listed in Table 3, antibody-based compositions or fragments thereof. Any molecule that is capable of binding a target antigen with high affinity can be used in the ASTR of a CAR. In some embodiments, the CAR may have more than one ASTR. These ASTRs may target two or more antigens or two or more epitopes of the same antigen. In some embodiments, the CAR is conditionally active. In some embodiments, the CAR is used to produce a genetically engineered cytotoxic cell carrying the CAR and capable of targeting the antigen bound by the ASTR.

Chimeric antigen receptors (CARs) are particularly useful in the treatment of cancers, though also therapeutically effective in treatment of a wide variety of other diseases and disorders. Non-limiting examples of disease categories that may be treated with CARs or CAR-based therapeutics include autoimmune disorders, B-cell mediated diseases, inflammatory diseases, neuronal disorders, cardiovascular disease and circulatory disorders, or infectious diseases. Not wishing to be bound by theory, CARs traditionally work by targeting antigens presented on the surface of or on the inside of cells to be destroyed e.g., cancer tumor cells, by the cytotoxic cell of the CAR.

Senescent Cell Surface Protein Antibodies

In some embodiments, the AAV particles may comprise nucleic acids which have been engineered to express of antibodies that selectively bind to surface marker proteins of senescent cells. For example, the antibodies may selectively bind to proteins that are in misfolded conformation. The binding antibodies may reduce the number of senescent cells and be used to treat age-related conditions, such as, but not limited to, Alzheimer's disease, cardiovascular disease, emphysema, sarcopenia, and tumorigenesis as well as conditions more cosmetic in nature such as signs of skin aging including wrinkling, sagging, discoloration, age-related tissue dysfunction, tumor formation, and other age-related conditions.

In some embodiments, the expressed antibodies binding to epitopes of senescent cell surface proteins may be, but are not limited to, such as prion epitopes presented by SEQ ID NO: 1-14 of International Publication No. WO2014186878; CD44 epitopes presented by SEQ ID NO: 47-51 of International Publication No. WO2014186878; TNFR epitopes presented by SEQ ID NO: 52-56 of International Publication No. WO2014186878; NOTCH1 epitope presented by SEQ ID NO: 57-61 of International Publication No. WO2014186878; FasR epitopes presented by SEQ ID NO: 62-66 of International Publication No. WO2014186878; epidermal growth factor epitopes presented by SEQ ID NO: 67-81 of International Publication No. WO2014186878; CD38 epitopes presented by SEQ ID NO: 82-86 of International Publication No. WO2014186878, the contents of each of which are herein incorporated by reference in their entirety.

In some embodiments, the expressed antibodies may comprise peptides binding to senescent cell surface prion proteins, such as, but not limited to, those presented by SEQ ID NO: 15-36 of International Publication No. WO2014186878, the contents of which are herein incorporated by reference in their entirety.

In some embodiments, the expressed antibody may be AMF-3a-118 or AMF 3d-19 (SEQ ID NO: 89-92 and 103-106 of International publication WO2014186878, respectively, the contents of which are herein incorporated by reference in their entirety) targeting senescent cell surface protein FasR. In some embodiments, the expressed antibody may be Ab c-120 (SEQ ID NO: 37-40 of International publication WO2014186878, the contents of which are herein incorporated by reference in their entirety) targeting senescent cell surface protein PrP.

Payload Antibodies

In some embodiments, the payload region of the AAV particle comprises one or more nucleic acid sequences encoding tau associated disease antibodies, variants or fragments thereof.

In some embodiments, the payload region of the AAV particle comprises one or more nucleic acid sequences encoding one or more of the payload antibody polypeptides listed in Table 3, or variants or fragments thereof. As used herein, “antibody polynucleotide” refers to a nucleic acid sequence encoding an antibody polypeptide.

In some embodiments, the payload region of the AAV particle comprises one or more nucleic acid sequences listed in Table 3, or variants or fragments thereof.

In some embodiments, the payload region of the AAV particle comprises a nucleic acid sequence encoding a payload antibody with at least 50% identity to one or more payload antibody polypeptides listed in Tables 3. The encoded antibody polypeptide may have 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to one or more of the payload antibody polypeptides listed in Table 3, or variants or fragments thereof.

In some embodiments, the full sequence of the encoded antibody polypeptide may have 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to one or more of the payload antibody polypeptides listed in Table 3, or variants or fragments thereof.

In some embodiments, the variable region sequence(s) of the encoded antibody polypeptide may have 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to one or more of the payload antibody polypeptides listed in Table 3, or variants or fragments thereof.

In some embodiments, the heavy chain of the encoded antibody polypeptide may have 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to one or more of the payload heavy chain antibody polypeptides listed in Table 3, or variants or fragments thereof.

In some embodiments, the light chain of the encoded antibody polypeptide may have 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to one or more of the payload light chain antibody polypeptides listed in Table 3, or variants or fragments thereof.

In some embodiments, the CDR region of the encoded antibody polypeptide may have 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the CDRs of one or more of the payload antibody polypeptides listed in Table 3, or variants or fragments thereof.

In some embodiments, the payload antibody has 90% identity to one or more of the antibody polypeptides listed in Table 3, or variants or fragments thereof.

In some embodiments, the payload antibody has 91% identity to one or more of the antibody polypeptides listed in Table 3, or variants or fragments thereof.

In some embodiments, the payload antibody has 92% identity to one or more of the antibody polypeptides listed in Table 3, or variants or fragments thereof.

In some embodiments, the payload antibody has 93% identity to one or more of the antibody polypeptides listed in Table 3, or variants or fragments thereof.

In some embodiments, the payload antibody has 94% identity to one or more of the antibody polypeptides listed in Table 3, or variants or fragments thereof.

In some embodiments, the payload antibody has 95% identity to one or more of the antibody polypeptides listed in Table 3, or variants or fragments thereof.

In some embodiments, the payload antibody has 96% identity to one or more of the antibody polypeptides listed in Table 3, or variants or fragments thereof.

In some embodiments, the payload antibody has 97% identity to one or more of the antibody polypeptides listed in Table 3, or variants or fragments thereof.

In some embodiments, the payload antibody has 98% identity to one or more of the antibody polypeptides listed in Table 3, or variants or fragments thereof.

In some embodiments, the payload antibody has 99% identity to one or more of the antibody polypeptides listed in Table 3, or variants or fragments thereof.

In some embodiments, the payload antibody has 100% identity to one or more of the antibody polypeptides listed in Table 3, or variants or fragments thereof.

In some embodiments, the payload region of the AAV particle comprises a nucleic acid sequence with at least 50% identity to one or more nucleic acid sequences listed in Table 3, or variants or fragments thereof. The payload nucleic acid sequence may have 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to one or more nucleic acid sequences listed in Table 3, or variants or fragments thereof.

In some embodiments, the payload nucleic acid sequence has 90% identity to one or more of the nucleic acid sequences listed in Table 3, or variants or fragments thereof.

In some embodiments, the payload nucleic acid sequence has 91% identity to one or more of the nucleic acid sequences listed in Table 3, or variants or fragments thereof.

In some embodiments, the payload nucleic acid sequence has 92% identity to one or more of the nucleic acid sequences listed in Table 3, or variants or fragments thereof.

In some embodiments, the payload nucleic acid sequence has 93% identity to one or more of the nucleic acid sequences listed in Table 3, or variants or fragments thereof.

In some embodiments, the payload nucleic acid sequence has 94% identity to one or more of the nucleic acid sequences listed in Table 3, or variants or fragments thereof.

In some embodiments, the payload nucleic acid sequence has 95% identity to one or more of the nucleic acid sequences listed in Table 3, or variants or fragments thereof.

In some embodiments, the payload nucleic acid sequence has 96% identity to one or more of the nucleic acid sequences listed in Table 3, or variants or fragments thereof.

In some embodiments, the payload nucleic acid sequence has 97% identity to one or more of the nucleic acid sequences listed in Table 3, or variants or fragments thereof.

In some embodiments, the payload nucleic acid sequence has 98% identity to one or more of the nucleic acid sequences listed in Table 3, or variants or fragments thereof.

In some embodiments, the payload nucleic acid sequence has 99% identity to one or more of the nucleic acid sequences listed in Table 3, or variants or fragments thereof.

In some embodiments, the payload nucleic acid sequence has 100% identity to one or more of the nucleic acid sequences listed in Table 3, or variants or fragments thereof.

TABLE 3 Tau Associated Disease Antibodies Type SEQ (PRT/ ID Ab ID Component DNA) Description Reference Len. NO Ab1 VH Signal DNA IPN002 (VH Signal) 57 1740 Ab2 VH Signal DNA PHF1 (VH Signal) 57 1741 Ab3 VH Constant DNA VH (constant - 969) 969 1742 Ab4 VH Constant DNA VH (constant - 972) 972 1743 Ab5 VH CDR PRT 7295-M6 HCDR WO2015122922; SEQ ID 10 1744 NO: 12 and 20 Ab6 VH CDR PRT 7295-M6 HCDR WO2015122922; SEQ ID 16 1745 NO: 13 and 21 Ab7 VH CDR PRT 7295-M6 HCDR WO2015122922; SEQ ID 4 1746 NO: 14 and 22 Ab8 VH CDR PRT 7297-2M1 HCDR WO2015122922; SEQ ID 16 1747 NO: 69 Ab9 VH CDR PRT 7298-M1 HCDR WO2015122922; SEQ ID 11 1748 NO: 28 Ab10 VH CDR PRT 7298-M1 HCDR WO2015122922; SEQ ID 16 1749 NO: 29 Ab11 VH CDR PRT 7298-M1 HCDR WO2015122922; SEQ ID 4 1750 NO: 30 Ab12 VH CDR PRT 7298-M2 HCDR WO2015122922; SEQ ID 10 1751 NO: 36 Ab13 VH CDR PRT 7298-M2 HCDR WO2015122922; SEQ ID 14 1752 NO: 37 Ab14 VH CDR PRT 7298-M2 HCDR WO2015122922; SEQ ID 8 1753 NO: 38 Ab15 VH CDR PRT 7299-M2 HCDR WO2015122922; SEQ ID 10 1754 NO: 44 and 60 Ab16 VH CDR PRT 7299-M2 HCDR WO2015122922; SEQ ID 16 1755 NO: 45 Ab17 VH CDR PRT 7299-M2 HCDR WO2015122922; SEQ ID 4 1756 NO: 46 and 62 Ab18 VH CDR PRT 7299-M5 HCDR WO2015122922; SEQ ID 10 1757 NO: 52 and 68 Ab19 VH CDR PRT 7299-M5 HCDR WO2015122922; SEQ ID 16 1758 NO: 53 Ab20 VH CDR PRT 7299-M5 HCDR WO2015122922; SEQ ID 10 1759 NO: 54 and 70 Ab21 VH CDR PRT 7299-M9 HCDR WO2015122922; SEQ ID 15 1760 NO: 61 Ab22 VH CDR PRT C10.2 HCDR1 WO2017009308; SEQ ID 13 1761 NO: 12, 20 and 28 Ab23 VH CDR PRT C10.2 HCDR2 WO2017009308; SEQ ID 16 1762 NO: 13 and 29 Ab24 VH CDR PRT C10.2 HCDR3 WO2017009308; SEQ ID 6 1763 NO: 14 and 30 Ab25 VH CDR PRT C5.2 HCDR2 WO2017009308; SEQ ID 16 1764 NO: 21 Ab26 VH CDR PRT C5.2 HCDR3 WO2017009308; SEQ ID 6 1765 NO: 22 Ab27 VH CDR PRT D1.2 HCDR1 WO2017009308; SEQ ID 13 1766 NO: 4 Ab28 VH CDR PRT D1.2 HCDR2 WO2017009308; SEQ ID 16 1767 NO: 5 Ab29 VH CDR PRT D1.2 HCDR3 WO2017009308; SEQ ID 6 1768 NO: 6 Ab30 VH CDR PRT HCDR1 U.S. Pat. No. 8,980,270; 5 1769 SEQ ID NO: 4 Ab31 VH CDR PRT HCDR1 U.S. Pat. No. 8,980,270; 5 1770 SEQ ID NO: 10 Ab32 VH CDR PRT HCDR2 U.S. Pat. No. 8,980,270; 17 1771 SEQ ID NO: 5 Ab33 VH CDR PRT HCDR2 U.S. Pat. No. 8,980,270; 17 1772 SEQ ID NO: 11 Ab34 VH CDR PRT HCDR2 WO2015081085; SEQ ID 32 1773 NO: 27 Ab35 VH CDR PRT HCDR3 U.S. Pat. No. 8,980,270; 8 1774 SEQ ID NO: 6 Ab36 VH CDR PRT HCDR3 U.S. Pat. No. 8,980,270; 8 1775 SEQ ID NO: 12 Ab37 VH CDR PRT HCDR3 WO2015081085; SEQ ID 11 1776 NO: 44 Ab38 VH CDR PRT IPN002 HCDR1 WO2014028777; SEQ ID 14 1777 NO: 84 Ab39 VH CDR PRT IPN002 HCDR2 WO2014028777; SEQ ID 32 1778 NO: 85 Ab40 VH CDR PRT IPN002 HCDR3 WO2014028777; SEQ ID 11 1779 NO: 86 Ab41 VH CDR PRT MC1 LCDR1 WO2016137811; SEQ ID 13 1780 NO: 6 Ab42 VH CDR PRT MC1 LCDR2 WO2016137811; SEQ ID 18 1781 NO: 7 Ab43 VH CDR PRT MC1 LCDR3 WO2016137811; SEQ ID 9 1782 NO: 8 Ab44 VH CDR PRT PT1 HCDR1 (Chothia) U.S. Pat. No. 9,371,376; 7 1783 SEQ ID NO: 19 Ab45 VH CDR PRT PT1 HCDR1 (Rabat) U.S. Pat. No. 9,371,376; 5 1784 SEQ ID NO: 7 Ab46 VH CDR PRT PT1 HCDR2 (Chothia) U.S. Pat. No. 9,371,376; 6 1785 SEQ ID NO: 20 Ab47 VH CDR PRT PT1 HCDR2 (Rabat) U.S. Pat. No. 9,371,376; 17 1786 SEQ ID NO. 8 Ab48 VH CDR PRT PT1 HCDR3 (Chothia) U.S. Pat. No. 9,371,376; 9 1787 SEQ ID NO: 21 Ab49 VH CDR PRT PT1 HCDR3 (Rabat) U.S. Pat. No. 9,371,376; 10 1788 SEQ ID NO: 9 Ab50 VH CDR PRT PT3 HCDR I (Chothia) U.S. Pat. No. 9,371,376; 7 1789 SEQ ID NO: 25 Ab51 VH CDR PRT PT3 HCDR1 (Rabat) U.S. Pat. No. 9,371,376; 5 1790 SEQ ID NO: 13 Ab52 VH CDR PRT PT3 HCDR2 (Chothia) U.S. Pat. No. 9,371,376; 5 1791 SEQ ID NO: 26 Ab53 VH CDR PRT PT3 HCDR2 (Rabat) U.S. Pat. No. 9,371,376; 16 1792 SEQ ID NO: 14 Ab54 VH CDR PRT PT3 HCDR3 (Chothia) U.S. Pat. No. 9,371,376; 9 1793 SEQ ID NO: 27 Ab55 VH CDR PRT PT3 HCDR3 (Rabat) U.S. Pat. No. 9,371,376; 10 1794 SEQ ID NO: 15 Ab56 VH PRT 7295-M6 VH WO2015122922; SEQ ID 125 1795 NO: 16 and 24 Ab57 VH PRT 7297-2M1 VH WO2015122922; SEQ ID 131 1796 NO: 72 Ab58 VH PRT 7298-M1 VH WO2015122922; SEQ ID 127 1797 NO: 32 Ab59 VH PRT 7298-M2 VH WO2015122922; SEQ ID 128 1798 NO: 40 Ab60 VH PRT 7299-M2 VH WO2015122922; SEQ ID 125 1799 NO: 48 Ab61 VH PRT 7299-M5 VH WO2015122922; SEQ ID 131 1800 NO: 56 Ab62 VH PRT 7299-M9 VH WO2015122922; SEQ ID 125 1801 NO: 64 Ab63 VH PRT C10.2 VH WO2017009308; SEQ ID 439 1802 NO: 16 Ab64 VH PRT C10.2 VH - 115 115 1803 Ab65 VH DNA C10.2 VH 345 1804 Bioinformatics Ab66 VH DNA C10.2 VH EMBOSS 345 1805 Ab67 VH DNA C10.2 VH Geneinfinity 345 1806 Ab68 VH DNA C10.2 VH 345 1807 GregThatcher Ab69 VH DNA C10.2 VH IDT 345 1808 Ab70 VH DNA C10.2 VH InSilico 345 1809 Ab71 VH DNA C10.2 VH MolBio 345 1810 Ab72 VH DNA C10.2 VH N2P 345 1811 Ab73 VH DNA C10.2 VH Snapgene 345 1812 Ab74 VH DNA C10.2 VH Vector NTT 345 1813 Ab75 VH PRT C5.2 VH WO2017009308; SEQ ID 439 1814 NO: 24 Ab76 VH PRT C8.3 VH WO2017009308; SEQ ID 439 1815 NO: 32 Ab77 VH PRT D1.2 VH WO2017009308; SEQ ID 451 1816 NO: 8 Ab78 VH PRT hC10.2 VH WO2017009308; SEQ ID 444 1817 NO: 35 Ab79 VH DNA IPN001 VH - 351 U.S. Pat. No. 8,980,270; 351 1818 SEQ ID NO: 18 Ab80 VH PRT IPN001 VH - 117 U.S. Pat. No. 8,980,270; 117 1819 SEQ ID NO: 14 Ab81 VH DNA IPN002 VH - 1377 1377 1820 Ab82 VH DNA IPN002 VH - 351 U.S. Pat. No. 8,980,270; 351 1821 SEQ ID NO: 20 Ab83 VH PRT IPN002 VH - 117 U.S. Pat. No. 8,980,270; 117 1822 SEQ ID NO: 16 Ab84 VH PRT IPN002 VH - 30 WO2014028777; SEQ ID 30 1823 NO: 83 Ab85 VH DNA IPN002 VH variant 1 U.S. Pat. No. 8,980,270; 351 1824 SEQ ID NO: 28 Ab86 VH PRT IPN002 VH variant 1 U.S. Pat. No. 8,980,270; 117 1825 SEQ ID NO: 36 Ab87 VH DNA IPN002 VH variant 2 U.S. Pat. No. 8,980,270; 351 1826 SEQ ID NO: 29 Ab88 VH PRT IPN002 VH variant 2 U.S. Pat. No. 8,980,270; 117 1827 SEQ ID NO: 37 Ab89 VH DNA IPN002 VH variant 3 U.S. Pat. No. 8,980,270; 351 1828 SEQ ID NO: 30 Ab90 VH PRT IPN002 VH variant 3 U.S. Pat. No. 8,980,270; 117 1829 SEQ ID NO: 38 Ab91 VH DNA IPN002 VH variant 4 U.S. Pat. No. 8,980,270; 351 1830 SEQ ID NO: 31 Ab92 VH PRT IPN002 VH variant 4 U.S. Pat. No. 8,980,270; 117 1831 SEQ ID NO: 39 Ab93 VH DNA MC1 VH - 1374 1374 1832 Ab94 VH DNA MC1 VH - 1326 WO2016137811; SEQ ID 1326 1833 NO: 12 Ab95 VH PRT MC1 VH - 458 458 1834 Ab96 VH PRT MC1 VH - 442 WO2016137811; SEQ ID 442 1835 NO: 2 Ab97 VH PRT MC1 VH - 116 WO2016137811; SEQ ID 116 1836 NO: 10 Ab98 VH DNA PHF1 VH - 1320 1320 1837 Ab99 VH DNA PHF1 VH - 1377 1377 1838 Ab100 VH DNA PHF1 VH - 351 351 1839 Ab101 VH DNA PHF1 VH - 699 699 1840 Ab102 VH DNA PHF1 VH - 717 717 1841 Ab103 VH DNA PHF1 VH - 744 744 1842 Ab104 VH DNA PHF1 VH - 753 753 1843 Ab105 VH PRT PHF1 VH - 459 459 1844 Ab106 VH DNA PHF1 VH+ 1383 1845 Ab107 VH DNA PT1 VH - 357 U.S. Pat. No. 9,371,376; 357 1846 SEQ ID NO: 31 Ab108 VH PRT PT1 VH - 119 U.S. Pat. No. 9,371,376; 119 1847 SEQ ID NO: 35 Ab109 VH DNA PT3 VH - 354 U.S. Pat. No. 9,371,376; 354 1848 SEQ ID NO: 33 Ab110 VH PRT PT3 VH - 118 U.S. Pat. No. 9,371,376; 118 1849 SEQ ID NO: 37 Ab111 VH DNA PT3 VH Bioinformatics 354 1850 Ab112 VH DNA PT3 VH Bioinformatics 354 1851 2 Ab113 VH DNA PT3 VH EMBOSS 354 1852 Ab114 VH DNA PT3 VH Geneinfinity 354 1853 Ab115 VH DNA PT3 VH Genescript 354 1854 Ab116 VH DNA PT3 VH IDT 354 1855 Ab117 VH DNA PT3 VH NUS 354 1856 Ab118 VH DNA PT3 VH NUS2 354 1857 Ab119 VH DNA PT3 VH NUS3 354 1858 Ab120 VH DNA PT3 VH Snapgene 354 1859 Ab121 VH PRT VH WO2015081085; SEQ ID 30 1860 NO: 25 Ab122 VL Signal DNA IPN002 (VL Signal) 57 1861 Ab123 VL Signal DNA PHF1 (VL Signal) 57 1862 Ab124 VL Signal DNA PHF1 (VL Signal 72) 72 1863 Ab125 VL Constant DNA VL (constant) 321 1864 Ab126 VL CDR PRT 7295-M6 LCDR WO2015122922; SEQ ID 16 1865 NO: 9 and 17 Ab127 VL CDR PRT 7295-M6 LCDR WO2015122922; SEQ ID 9 1866 NO: 11 and 19 Ab128 VL CDR PRT 7297-2M1 LCDR WO2015122922; SEQ ID 11 1867 NO: 65 Ab129 VL CDR PRT 7297-2M1 LCDR WO2015122922; SEQ ID / 1868 NO: 66 Ab130 VL CDR PRT 7297-2M1 LCDR WO2015122922; SEQ ID 8 1869 NO: 67 Ab131 VL CDR PRT 7298-M1 LCDR WO2015122922; SEQ ID 15 1870 NO: 25 and 33 Ab132 VL CDR PRT 7298-M1 LCDR WO2015122922; SEQ ID 7 1871 NO: 26 and 34 Ab133 VL CDR PRT 7298-M1 LCDR WO2015122922; SEQ ID 9 1872 NO: 27 and 35 Ab134 VL CDR PRT 7299-M2 LCDR WO2015122922; SEQ ID 16 1873 NO: 41 Ab135 VL CDR PRT 7299-M2 LCDR WO2015122922; SEQ ID 7 1874 NO: 42 Ab136 VL CDR PRT 7299-M2 LCDR WO2015122922; SEQ ID 9 1875 NO: 43 Ab137 VL CDR PRT 7299-M5 LCDR WO2015122922; SEQ ID 16 1876 NO: 49 and 57 Ab138 VL CDR PRT 7299-M5 LCDR WO2015122922; SEQ ID 7 1877 NO: 50 and 58 Ab139 VL CDR PRT 7299-M5 LCDR WO2015122922; SEQ ID 9 1878 NO: 51 Ab140 VL CDR PRT 7299-M9 LCDR WO2015122922; SEQ ID 8 1879 NO: 59 Ab141 VL CDR PRT C10.2 LCDR1 WO2017009308; SEQ ID 11 1880 NO: 9 and 25 Ab142 VL CDR PRT C10.2 LCDR2 WO2017009308; SEQ ID 7 1881 NO: 10 and 18 Ab143 VL CDR PRT C10.2 LCDR3 WO2017009308; SEQ ID 7 1882 NO: 11 and 19 Ab144 VL CDR PRT C5.2 LCDR1 WO2017009308; SEQ ID 11 1883 NO: 17 Ab145 VL CDR PRT C8.3 LCDR2 WO2017009308; SEQ ID / 1884 NO: 26 Ab146 VL CDR PRT C8.3 LCDR3 WO2017009308; SEQ ID 7 1885 NO: 27 Ab147 VL CDR PRT D1.2 LCDR1 WO2017009308; SEQ ID 16 1886 NO: 1 Ab148 VL CDR PRT D1.2 LCDR2 WO2017009308; SEQ ID 7 1887 NO: 2 Ab149 VL CDR PRT D1.2 LCDR3 WO2017009308; SEQ ID 7 1888 NO: 3 Ab150 VL CDR PRT IPN002 LCDR1 WO2014028777; SEQ ID 15 1889 NO: 55 Ab151 VL CDR PRT IPN002 LCDR2 WO2014028777; SEQ ID 32 1890 NO: 56 Ab152 VL CDR PRT IPN002 LCDR3 WO2014028777; SEQ ID 10 1891 NO: 57 Ab153 VL CDR PRT LCDR1 U.S. Pat. No. 8,980,270; 16 1892 SEQ ID NO: 1 Ab154 VL CDR PRT LCDR1 U.S. Pat. No. 8,980,270; 16 1893 SEQ ID NO: 7 Ab155 VL CDR PRT LCDR1 WO2015081085; SEQ ID 15 1894 NO: 46 Ab156 VL CDR PRT LCDR2 U.S. Pat. No. 8,980,270; 7 1895 SEQ ID NO: 2 Ab157 VL CDR PRT LCDR2 WO2015081085; SEQ ID 32 1896 NO: 47 Ab158 VL CDR PRT LCDR3 U.S. Pat. No. 8,980,270; 9 1897 SEQ ID NO: 3 and 9 Ab159 VL CDR PRT MC1 LCDR1 WO2016137811; SEQ ID 16 1898 NO: 3 Ab160 VL CDR PRT MC1 LCDR2 WO2016137811; SEQ ID 8 1899 NO: 4 Ab161 VL CDR PRT MC1 LCDR3 WO2016137811; SEQ ID 9 1900 NO: 5 Ab162 VL CDR PRT PT1 LCDR1 (Chothia) U.S. Pat No. 9,371,376; 12 1901 SEQ ID NO: 22 Ab163 VL CDR PRT PT1 LCDR1 (Rabat) U.S. Pat No. 9,371,376; 16 1902 SEQ ID NO: 10 Ab164 VL CDR PRT PT1 LCDR2 (Chothia) U.S. Pat No. 9,371,376; 3 1903 SEQ ID NO: 23 Ab165 VL CDR PRT PT1 LCDR2 (Rabat) U.S. Pat No. 9,371,376; 7 1904 SEQ ID NO: 11 Ab166 VL CDR PRT PT1 LCDR3 (Chothia) U.S. Pat No. 9,371,376; 7 1905 SEQ ID NO: 24 Ab167 VL CDR PRT PT1 LCDR3 (Rabat) U.S. Pat No. 9,371,376; 9 1906 SEQ ID NO. 12 Ab168 VL CDR PRT PT3 LCDR1 (Chothia) U.S. Pat No. 9,371,376; 7 1907 SEQ ID NO: 28 Ab169 VL CDR PRT PT3 LCDR1 (Rabat) U.S. Pat No. 9,371,376; 11 1908 SEQ ID NO: 16 Ab170 VL CDR PRT PT3 LCDR2 (Chothia) U.S. Pat No. 9,371,376; 3 1909 SEQ ID NO: 29 Ab171 VL CDR PRT PT3 LCDR2 (Rabat) U.S. Pat No. 9,371,376; 7 1910 SEQ ID NO: 17 Ab172 VL CDR PRT PT3 LCDR3 (Chothia) U.S. Pat No. 9,371,376; 6 1911 SEQ ID NO: 30 Ab173 VL CDR PRT PT3 LCDR3 (Rabat) U.S. Pat No. 9,371,376; 10 1912 SEQ ID NO: 18 Ab174 VL PRT 7295-M6 VL WO2015122922; SEQ ID 122 1913 NO: 15 and 23 Ab175 VL PRT 7297-2M1 VL WO2015122922; SEQ ID 116 1914 NO: 71 Ab176 VL PRT 7298-M1 VL WO2015122922; SEQ ID 121 1915 NO: 31 and 39 Ab177 VL PRT 7299-M2 VL WO2015122922; SEQ ID 122 1916 NO: 47 Ab178 VL PRT 7299-M5 VL WO2015122922; SEQ ID 122 1917 NO: 55 Ab179 VL PRT 7299-M9 VL WO2015122922; SEQ ID 122 1918 NO: 63 Ab180 VL PRT C10.2 VL - 107 107 1919 Ab181 VL PRT C10.2 VL -214 WO2017009308; SEQ ID 214 1920 NO: 15 Ab182 VL DMA C10.2 VL 321 1921 Bioinformatics Ab183 VL DNA C10.2 VL EMBOSS 321 1922 Ab184 VL DNA C10.2 VL GeneInfinity 321 1923 Ab185 VL DNA C10.2 VL 321 1924 GregThatcher Ab186 VL DNA C10.2 VL IDT 321 1925 Ab181 VL DNA C10.2 VL InSilico 321 1926 Ab188 VL DNA C10.2 VL MolBio 321 1927 Ab189 VL DNA C10.2 VLN2P 321 1928 Ab190 VL DNA C10.2 VL Snapgene 321 1929 Ab191 VL DNA C10.2 VL Vector NTI 321 1930 Ab192 VL PRT C5.2. VL WO2017009308; SEQ ID 214 1931 NO: 23 Ab193 VL PRT C8.3 VL WO2017009308; SEQ ID 214 1932 NO: 31 Ab194 VL PRT D1.2 VL WO2017009.308; SEQ ID 219 1933 NO: 7 Ab195 VL PRT D1.2* VL WO2017009308; SEQ ID 219 1934 NO: 34 Ab196 VL PRT hC10.2 VL WO2017009308; SEQ ID 214 1935 NO: 36 Ab197 VL DNA IPN001 VL - 336 U.S. Pat No. 8,980,270; 336 1936 SEQ ID NO: 17 Ab198 VL PRT IPN001 VL U.S. Pat No. 8,980,270; 112 1937 SEQ ID NO. 13 Ab199 VL PRT IPN002 VL WO2014028777; SEQ ID 23 1938 NO: 54 Ab200 VL DNA IPN002 VL - 336 U.S. Pat No. 8,980,270; 336 1939 SEQ ID NO. 19 Ab201 VL DNA IPN002 VL - 714 714 1940 Ab202 VL PRT IPN002 VL - 112 U.S. Pat No. 8,980,270; 112 1941 SEQ ID NO: 15 Ab203 VL DNA IPN002 VL variant 1 U.S. Pat No. 8,980,270; 336 1942 SEQ ID NO: 32 Ab204 VL PRT IPN002 VL variant 1 U.S. Pat No. 8,980,270; 112 1943 SEQ ID NO: 40 Ab205 VL DNA IPN002 VL variant 2 U.S. Pat No. 8,980,270; 336 1944 SEQ ID NO: 33 Ab206 VL PRT IPN002 VL variant 2 U.S. Pat No. 8,980,270; 112 1945 SEQ ID NO: 41 Ab207 VL DNA IPN002 VL variant 3 U.S. Pat No. 8,980,270; 336 1946 SEQ ID NO: 34 Ab208 VL PRT IPN002 VL variant 3 U.S. Pat No. 8,980,270; 112 1947 SEQ ID NO: 42 Ab209 VL DNA IPN002 VL variant 4 U.S. Pat No. 8,980,270; 336 1948 SEQ ID NO: 35 Ab210 VL PRT IPN002 VL variant 4 U.S. Pat No. 8,980,270; 112 1949 SEQ ID NO: 43 Ab211 VL DNA MC1 VL - 714 714 1950 Ab212 VL DNA MC1 VL - 717 717 1951 Ab213 VL DNA MC1 VL - 657 WO2016137811; SEQ ID 657 1952 NO: 11 Ab214 VL PRT MC1 VL - 238 238 1953 Ab215 VL PRT MC1 VL - 219 WO2016137811; SEQ ID 219 1954 NO: 1 Ab216 VL PRT MC1 VL - 112 WO2016137811; SEQ ID 112 1955 NO: 9 Ab217 VL DNA PHF1 VL - 339v1 339 1956 Ab218 VL DNA PHF1 VL - 339v2 339 1957 Ab219 VL DNA PHF1 VL - 396 396 1958 Ab220 VL DNA PHF1 VL - 657 657 1959 Ab221 VL DNA PHF1 VL - 660 660 1960 Ab222 VL DNA PHF1 VL - 678 678 1961 Ab223 VL DNA PHF1 VL - 714 714 1962 Ab224 VL DNA PHF1 VL - 720 720 1963 Ab225 VL PRT PHF1 VL - 239 239 1964 Ab226 VL DNA PHF1 VL+ (732) 732 1965 Ab227 VL DNA PHF1 VL+ (747) 747 1966 Ab228 VL DNA PT1 VL - 336 U.S. Pat No. 9,371,376; 336 1967 SEQ ID NO: 32 Ab229 VL PRT PT1 VL - 112 U.S. Pat No. 9,371,376; 112 1968 SEQ ID NO: 36 Ab230 VL DNA PT3 VL - 321 U.S. Pat No. 9,371,376; 321 1969 SEQ ID NO: 34 Ab231 VL PRT PT3 VL - 107 U.S. Pat No. 9,371,376; 107 1970 SEQ ID NO: 38 Ab232 VL DNA PT3 VL Bioinformatics 321 1971 Ab233 VL DNA PT3 VL Bioinformatics 321 1972 2 Ab234 VL DNA PT3 VL EMBOSS 321 1973 Ab235 VL DNA PT3 VL Geneinfinity 321 1974 Ab236 VL DNA PT3 AT Genescript 321 1975 Ab237 VL DNA PT3 VL IDT 321 1976 Ab238 VL DNA PT3 VL NUS 321 1977 Ab239 VL DNA PT3 VL NUS2 321 1978 Ab240 VL DNA PT3 VL NUS3 321 1979 Ab241 VL DNA PT3 VL Snapgene 321 1980 Ab242 VL PRT VL WO2015081085; SEQ ID 23 1981 NO: 45 Ab243 Fab PRT AT8 Fab1 Malia, T. J. et al, “Epitope 18 1982 mapping and structural basis for the recognition of phosphorylated tan by the anti-tau antibody AT8”, Proteins 84 (4), 427-434 (2016), Accession number 5E2V_P Ab244 Fab PRT AT8 Fab2 Malta, T. J. et al, “Epitope 18 1983 mapping and structural basis for the recognition of phosphorylated tau by the anti-tau antibody AT8”, Proteins 84 (4), 427-434 (2016), Accession number 5E2W_P Ab245 Full DNA MC1 Furin 2A - 2168 WO2015035190; SEQ ID 2168 1984 antibody NO: 2 Ab246 Full PRT MC1 Furin 2A - 718 WO2015035190; SEQ ID 718 1985 antibody NO: 4 Ab247 Full DNA MC1 optimized seq WQ2015035190; SEQ ID 2168 1986 antibody NO: 6 Ab248 Full DNA PHF1 Furin 2A - 2174 W02015035190; SEQ ID 2174 1987 antibody NO: 1 Ab249 Full PRT PHF1 Furin 2A - 726 W02015035190; SEQ ID 720 1988 antibody NO: 3 Ab250 Full DNA PHF1 optimized seq W02015035190; SEQ ID 2174 1989 antibody NO: 5 Ab251 VH DNA PT3 348 2241 Ab252 VH Constant DNA VH (constant - 309) 309 2242 Ab253 VH Constant DNA VH (constant - 291) 291 2243 Ab254 VH DNA PHF1 VH-435 435 2169 Ab255 VH DNA PHF1 VH-408 408 2170

In some embodiments, tube payload region of the AAV particle comprises a nucleic acid sequence encoding a polypeptide which is an antibody, an antibody-based composition, or a fragment thereof. As a non-limiting example, the antibody may be one or more of the polypeptides listed in Table 3, or variants or fragments thereof. As another non-limiting example, the antibody may be one or more of the heavy chain sequences listed in Table 3. As a non-limiting example, the antibody may be one or more of the light chain sequences listed in Table 3, or variants or fragments thereof.

In some embodiments, the payload region of the AAV particle comprises a nucleic acid sequence encoding a polypeptide comprising a heavy chain and a light chain sequence listed in Table 3, or variants or fragments thereof. The payload region may also comprise a linker between the heavy and light chain sequences. The linker may be a sequence known in the art or described in Table 2.

In some embodiments, the payload region of the AAV particle comprises a nucleic acid sequence encoding a polypeptide comprising a heavy chain and a light chain sequence listed in Table 3, or variants or fragments thereof, where the heavy chain sequence is from a different antibody than the light chain sequence. The payload region may also comprise a linker between the heavy and light chain sequences. The linker may be a sequence known in the art or described in Table 2.

In some embodiments, the payload region comprises, in the 5′ to 3′ direction, an antibody light chain sequence, a linker and a heavy chain sequence. In another embodiment, the linker is not used.

In some embodiments, the payload region comprises a nucleic acid sequence encoding, in the 5′ to 3′ direction, an antibody light chain sequence from Table 3, a linker from Table 2 and a heavy chain sequence from Table 3. Non-limiting examples are included in Tables 4-6 and Tables 15-91.

In some embodiments, the payload region comprises, in the 5′ to 3′ direction, an antibody heavy chain sequence, a linker region (may comprise one or more linkers) and a light chain sequence. In another embodiment, the linker is not used.

In some embodiments, the payload region comprises a nucleic acid sequence encoding, in the 5′ to 3′ direction, an antibody heavy chain sequence from Table 3, one or more linkers from Table 2, and a light chain sequence from Table 3. Non-limiting examples are included in Tables 4-6 and Tables 15-91.

In some embodiments, the payload region comprises a nucleic acid sequence encoding a single heavy chain. As a non-limiting example, the heavy chain is an amino acid sequence or fragment thereof described in Table 3.

Shown in Table 3 are a listing of antibodies and their polynucleotides and/or polypeptides sequences. These sequences may be encoded by or included in the AAV particles of the present disclosure. Variants or fragments of the antibody sequences described in Table 3 may be utilized in the AAV particles of the present disclosure.

In some embodiments, the AAV particles may comprise a viral genome, wherein one or more components may be codon-optimized. Codon-optimization may be achieved by any method known to one with skill in the art such as, but not limited to, by a method according to Genescript, EMBOSS, Bioinformatics. NUS, NUS2, Geneinfinity, IDT, NUS3, GregThatcher, Insilico, Molbio, N2P, Snapgene, and/or VectorNTI. Antibody heavy and/or light chain sequences within the same viral genome may be codon-optimized according to the same or according to different methods.

In some cases, the payload region of the AAV particles may encode one or more isoforms or variants of heavy and light chain antibody domains. Such variants may be humanized or optimized antibody domains comprising one or more complementarity determining regions (CDRs) from the heavy and light chains listed in Table 3. CDRs of the antibodies encoded by the viral genomes of the present disclosure may be 50%, 60%, 70%, 80%, 90%, 95% identical to CDRs listed in or incorporated in the sequences of Table 3. Methods of determining CDRs are well known in the art and are described herein. Payload regions may encode antibody variants with one or more heavy chain variable domain (V_(H)) or light chain variable domain (V_(L)) derived from the antibody sequences in Table 3. In some cases, such variants may include bispecific antibodies. Bispecific antibodies encoded by payload regions may comprise variable domain pairs from two different antibodies.

In some embodiments, the AAV particles may comprise a heavy and a light chain of an antibody described herein and two promoters. As a non-limiting example, the AAV particles may comprise a nucleic acid sequence of a genome as described in FIG. 1 or FIG. 2 of US Patent Publication No. US20030219733, the contents of which are herein incorporated by reference in their entirety. As another non-limiting example, the AAV particles may be a dual-promoter AAV for antibody expression as described by Lewis et al. (J. of. Virology, September 2002, Vol. 76(17), p 8769-8775; the contents of which are herein incorporated by reference in their entirety).

Payload regions of the viral genomes may encode any anti-tau antibodies, or tau-associated antibodies, not limited to those described in Table 3, including antibodies that are known in the art and/or antibodies that are commercially available. This may include fragments of such antibodies or antibodies that have been developed to comprise one or more of such fragments [e.g., variable domains or complementarity determining regions (CDRs)]. Anti-tau antibodies that may be encoded by payloads include, but are not limited to, AT8 (pSer²⁰²/pThr²⁰⁵; ThermoFisher, Waltham, Mass.; described in International Publication No. WO1995017429, the contents of which are herein incorporated in their entirety), AT100 (pThr²¹²/pSer²¹⁴; ThermoFisher, Waltham, Mass.; described in U.S. Pat. No. 6,121,003, the contents of which are herein incorporated in their entirety), AT180 (pThr²³¹; ThermoFisher, Waltham, Mass.; described in International Publication No. WO1995017429, the contents of which are herein incorporated by reference in their entirety), MC-1 (or MC1) (Tau^(2-18/312-342) conformational antibody; as described in international Publication WO199620218, the contents of which are herein incorporated by reference in their entirety), MC-6 (pSer²³⁵; described in U.S. Pat. No. 5,811,310, the contents of which are herein incorporated in their entirety). TG-3 (pThr²³¹; described in Jicha, G A et al., 1997 J Neurochem 69(5):2087-95, the contents of which are herein incorporated by reference in their entirety), CP13 (pSer²⁰²), CP27 (human Tau¹³⁰⁻¹⁵⁰), Tau12 (human Tau⁹⁻¹⁸; Abcam, Cambridge, Mass.), TG5 (Tau²²⁰⁻²⁴²; described in U.S. Pat. No. 5,811,310), DA9 (Tau¹⁰²⁻¹⁴⁰; described in U.S. Pat. No. 5,811,310), PHF1 (or PHF-1) (pSer³⁹⁶/pSer⁴⁰⁴; described in International Publication WO199620218), Alz50 (Tau⁷⁻⁹ and Tau³¹²⁻³⁴² conformational epitope; described in U.S. Pat. No. 5,811,310 and Carmel, G et al 1996 J Biol Chem 271(51):32780-32795 and Jicha, G A et al, 1997 J Neurosci Res 48(2):128-132, the contents of each of which are herein incorporated by reference in their entirety). Tau-1 (de-phosphorylated Ser¹⁹⁵/Ser¹⁹⁸/Ser¹⁹⁹/Ser²⁰²; ThermoFisher, Waltham, Mass.), Tau46 (Tau⁴⁰⁴⁻⁴⁴¹; Abcam, Cambridge, Mass.), pS199 (ThermoFisher, Waltham, Mass.), pT205, pS396 (ThermoFisher, Waltham, Mass.; described in U.S. Pat. No. 8,647,631, the contents of which are herein incorporated by reference in their entirety), pS404 (ThermoFisher, Waltham, Mass.; described in U.S. Pat. No. 8,647,631, the contents of which are herein incorporated by reference in their entirety), pS422 (ThermoFisher, Waltham, Mass.), A0024 (hTau²⁴³⁻⁴⁴¹; Dako, Glostrup, Denmark), HT7 (hTau¹⁵⁹⁻¹⁶³; ThermoFisher, Waltham, Mass.), Tau2 (hTau⁵²⁻⁶⁸; Abcam, Cambridge, Mass.), AD2 (pSer³⁹⁶/pSer⁴⁰⁴; Bio-Rad Laboratories, Hercules, Calif.), AT120 (hTau²¹⁶⁻²²⁴; described in U.S. Pat. No. 5,843,779, the contents of which are herein incorporated by reference in their entirety), AT270 (pThr¹⁸¹; ThermoFisher, Waltham, Mass.), 12E8 (pSer²⁶² and/or Ser³⁵⁶), K9JA (hTau²⁴³⁻⁴⁴¹; Dako, Caprinteria, Calif.), TauC3 (hTau Asp441; Santa Cruz Biotechnology, Dallas, Tex.; described in United States Patent Publication US20120244174 and Gamblin, T C et al 2003 PNAS 100(17):10032-7, the contents of each of which are herein incorporated by reference in their entirety). 4E6G7 (pSer³⁹⁶/pSer⁴⁰⁴; described in United States Patent Publication No. US2010316564 and Congdon, E. E. et al., 2016. Molecular Neurodegeneration August 30; 11(1):62, the contents of which are herein incorporated by reference in their entirety), 6B2 and variants thereof, described in International Patent Publication WO2016007414, the contents of which are herein incorporated by reference in their entirety. RZ3 (pThr²³¹), PG5 (pSer⁴⁰⁹), BT2 (pS^(199/202)), DA31 (Tau¹⁵⁰⁻¹⁹⁰), CP9 (pThr²³¹) Ta1505 (phospho site between Tau⁴¹⁰⁻⁴²¹, particularly pSer⁴¹³ as described in United States Patent Publication US20150183854 and Umeda, T. et al., 2015. Ann Clin Trans Neurol 2(3): 241-255, the contents of each of which are herein incorporated by reference in their entirety), PHF-6 (pThr²³¹, as described in Hoffman R et al., 1997. Biochemistry 36:8114-8124, the contents of which are herein incorporated by reference in their entirety), PHF-13 (pSer³⁹⁶, as described in Hoffman R et al., 1997. Biochemistry 36; 8114-8124), 16B5 (Tau²⁵⁻⁴⁶, as described in United States Publication US20160031976, the contents of which are herein incorporated by reference in their entirety), DC8E8 (as described in United States Patent Publication US20150050215, the contents of which are herein incorporated by reference in their entirety), PT1 or PT3 (as described in U.S. Pat. No. 9,371,376, the contents of which are herein incorporated by reference in their entirety), 4G11 (Tau⁵⁴⁻⁶⁴, as described in International Publication WO2016137950, the contents of which are herein incorporated by reference in their entirety). 1A6 (Tau⁷⁻¹⁷ and Tau²¹⁵⁻²²⁰, as described in International Publication WO2016137950), Tau15 or Tau81 (as described in International Publication WO2016055941, the contents of which are herein incorporated by reference in their entirety), TOC-1 (dimerized or aggregated tau, as described in International Publication WO2012149365, the contents of which are herein incorporated by reference in their entirety), pS4041gG2a/k (Neotope Biosciences, South San Francisco, Calif.; as described in Ittner et al., 2015. Neurochemistry 132:135-145, the contents of which are herein incorporated by reference in their entirety), TOMA (tau oligomer monoclonal antibody; as described in U.S. Pat. Nos. 8,778,343 and 9,125,846, International Publications WO2012051498 and WO2011026031, or United States Publication Nos. US20150004169 and US20150322143, and Castillo-Carranza, D L et al., 2014 J Neurosci 34(12)4260-72, the contents of each of which are herein incorporated by reference in their entirety), TTC-99 (oligomeric tau), BMS-986168 (as described in United States Patent Publication US2014294831, International Publication WO2015081085 and U.S. Pat. No. 8,980,271, the contents of which are herein incorporated by reference in their entirety), 3H3 (pan-amyloid epitope; described in Levites, Y et al 2015 J Neurosci 35(16)6265-76, the contents of which are herein incorporated by reference in their entirety), cis-pT231 (described in International Publications WO2012149334 and WO2011056561, the contents of which are herein incorporated by reference in their entirety), CP-3 (pSer²¹⁴; described in Jicha et al 1999 J Neurosci 19(17):7486-94, the contents of which are herein incorporated by reference in their entirety). TNT1 (Tau²⁻¹⁸; as described in United States Patent Publication 20160031978, the contents of which are herein incorporated by reference in their entirety), Tau-nY29 (nTyr²⁹; described in Reynolds M R, et al., 2006 J Neurosci 26(42):10636-45, the contents of which are herein incorporated by reference in their entirety), Tau-nY197 (nTyr¹⁹⁷; described in Reyes, J F et al., 2012 Acta Neuropathol 123(1):119-32, the contents of which are herein incorporated by reference in their entirety), Tau-nY394 (nTyr³⁹⁴; described in Reyes, J F et al 2012), 4E4 (Tau³³⁷⁻³⁴³ Tau³⁸⁷⁻³⁹⁷; described in International Publication WO2012049570 and United States Patent Publication US20150252102, the contents of each of which are herein incorporated by reference in their entirety), ADx210 (described in United States Patent Publication US20140161875, the contents of which are herein incorporated by reference in their entirety), ADx215 (described in United States Patent Publication US20140161875), ADx202 (as described in International Publication WO2015004163, the contents of which are herein incorporated by reference in their entirety), AP422 (pSer⁴²²; described in Hasegawa, M et al 1996 FEBS Lett 384:25-30, the contents of which are herein incorporated by reference in their entirety), Tau5 (Tau²¹⁰⁻²⁴¹), RTA2 (Tau²⁷³⁻²⁸³), RTAC (Tau⁴²⁶⁻⁴⁴¹), RTA1 (Tau²⁵⁷⁻²⁷⁴), T46 (Tau³⁹⁴⁻⁴³²), T49, MIGT4, O.BG.15, 525, 3-39, 4F1, MapTau (Tau⁹⁴⁻¹⁰⁸; SMI Covance), T1, HYB33801 (Tau⁵⁻¹²), Tau13 (Tau²⁻¹⁸), B11E8, 5J20 (14-3-3 tau), DC25 (Tau³⁴⁷⁻³⁵³), DC39N1 (Tau⁴⁵⁻⁷³), DC-11 (Tau³²¹⁻³⁹¹; described in U.S. Pat. No. 7,746,180, the contents of which are herein incorporated by reference in their entirety), DC39 (Tau⁴⁰¹⁻⁴¹¹), DC4R, n847 (nitrated tau), SPM452, T14. 1E1/A6 (Tau²⁷⁵⁻²⁹¹), 5E2, 8E6/C11 (Tau²⁰⁹⁻²²⁴), 2E12 (pT231), NFT200, 248E5 (Tau³⁻²¹⁴), IG2 (Thr¹⁷⁵, Thr¹⁸¹, Thr²³¹; as described in International Publication WO2016041553, the contents of which are herein incorporated by reference in their entirety), YP3 (as described in WO2007019273, the contents of which are herein incorporated by reference in their entirety), YP4 (as described in WO2007019273) and 14-3-3 Tau (pSer 14-3-3 binding motif; Abcam, Cambridge, Mass.). Further, anti-tau antibodies may be any of those listed in the antibody section of Alzforum.org or at the Antibody Resource Page.com, the contents of each of which are herein incorporated by reference in their entirety. Further, anti-tau antibodies may be any commercially available anti-tau antibody. Additional antibodies may include any of those taught in Petry, F. R. et al., 2014. PLoS One 9(5): e94251, the contents of which are herein incorporated by reference in their entirety. In one example, such antibodies may include any of those described in Jicha, G. A. et al., 1997. Journal of Neuroscience Research 48:128-132, the contents of which are herein incorporated by reference in their entirety. One such antibody, MC-1 (or MC1), recognizes distinct conformations of tau that are associated with neurological disease.

In some embodiments, the AAV particles may have a payload region comprising any of the anti-tau antibodies as described in International Publication WO2017189963, the contents of which are herein incorporated by reference in their entirety. As a non-limiting example, the payload region may comprise one or more of the anti-tau antibodies as described in Table 3 of International Publication WO2017189963. In some embodiments, the payload region encodes one or more anti-tau antibodies selected from SEQ ID NO: 2948-4269 as described in WO2017189963.

In some embodiments, payloads may encode anti-tau antibodies (or fragments thereof) taught in United States Publication No. US2014294831, the contents of which are herein incorporated by reference in their entirety. Such antibodies may include IPN001 and/or IPN002 antibodies or fragments of such antibodies. In some cases, variable domains of IPN002 as presented in FIGS. 2A and 2B of US2014294831 may be used (e.g., incorporated into another antibody). In some cases, CDR regions of IPN002 as underlined in FIGS. 2A and 2B may be used (e.g., incorporated into another antibody or used to prepare humanized versions of IPN002). In some cases, anti-tau antibodies may include any of the IPN001 or IPN002 antibody variants taught in US2014294831 (e.g., in FIGS. 9-16 of that publication). In some embodiments, this antibody is also referred to as BMS-986168.

In some cases, payloads may encode anti-tau antibodies (or fragments thereof) taught in Otvos, L. et al., 1994. J Neurosci. Res 39(6):669-73, the contents of which are herein incorporated by reference in their entirety. Such antibodies may include monoclonal antibody PHF-1 or fragments thereof. The PHF-1 antibody binds to tau paired helical filaments, a pathological conformation of tau, found in certain neurological disorders, including Alzheimer's disease. Further, antibody affinity is increased when either serine 396 or serine 404 of tau is phosphorylated and even further increased when both are phosphorylated.

In some embodiments, payloads may encode anti-tau antibodies (or fragments thereof) taught in U.S. Pat. No. 5,811,310, the contents of which are herein incorporated by reference in their entirety. Such embodiments may include monoclonal antibodies PHF-1 or MC1 or fragments thereof. MC1 is a conformational antibody binding to the epitopes presented in Jicha, G. A., et al., 1997. J Neurosci Res 48(128-132).

In some embodiments, payloads may encode anti-tau antibodies (or fragments thereof) taught in International Publication Number WO2015035190, the contents of which are herein incorporated by reference in their entirety. Such embodiments may include, but are not limited to, antibodies PHF-1 or MC1 or fragments thereof. Viral genomes of the AAV particles of the present disclosure may comprise or encode any of SEQ ID NO: 1-6 of WO2015035190.

In some embodiments, viral genomes may encode anti-tau antibody MC1 scFv as described in Vitale et al 2018, (Acta Neuropath Commun. 6:82) the contents of which are herein incorporated by reference in their entirety.

In some embodiments, viral genomes may encode anti-tau antibody MC1 as described in International Publication WO2016137811, the contents of which are herein incorporated by reference in their entirety.

Anti-tau antibodies (or fragments thereof) encoded by viral genomes may include antibodies that bind to one or more of the epitopes presented in Otvos, L. et al., 1994. J Neurosci. Res 39(6):669-73 (e.g., any of those presented in Table 1 of that publication).

In some embodiments, payloads may encode anti-tau antibodies (or fragments thereof) taught in U.S. Pat. No. 7,746,180, the contents of which are herein incorporated by reference in their entirety. Such embodiments may include antibody DC-11 or fragments thereof.

In some embodiments, the antibodies encoded by the viral genomes of the present disclosure may target any of the antigenic regions or epitopes described in United States Patent Publication No US2008050383 or US20100316564, the contents of which are herein incorporated by reference in their entirety. In some embodiments, the antibody targets pS396/pS404. Such embodiments may include antibody 4E6 and/or variants or fragments thereof. The affinity of antibody 4E6 for soluble PHF and its ability to reduce soluble phospho tau has been described in Congdon, E. E. et al., 2016. Molecular Neurodegeneration August 30; 11(1):62, the contents of which are herein incorporated by reference in their entirety.

In some embodiments, the antibodies encoded by the viral genomes of the present disclosure may target any of the antigenic regions or epitopes described in International Patent Publication WO1998022120, the contents of which are herein incorporated by reference in their entirety. In some embodiments, the antibody may be PHF-6 (pT231), or fragments or variants thereof. In another embodiment, the antibody may be PHF-13 (pS396), or a fragment of variant thereof. These antibodies are further described in Hoffman et al., 1997. Biochemistry 36: 8114-8124, the contents of which are herein incorporated by reference in their entirety.

In some embodiments, the antibodies encoded by the viral genomes of the present disclosure may target any of the antigenic regions or epitopes described in International Publication WO2016126993, the contents of which are herein incorporated by reference in their entirety. The antibodies may be derived from any of the tau epitopes described in Table A of WO2016126993. In some embodiments, the antibody of the present disclosure may comprise any of the sequences listed in Table B or Table 1 of WO2016126993.

In some embodiments, the antibodies encoded by the viral genomes of the present disclosure may target any of the antigenic regions or epitopes described in United States Patent Publication US20120244174, the contents of which are herein incorporated by reference in their entirety. In some embodiments, the antibody may bind to caspase-cleaved tau. In some embodiments, the epitope for antibodies targeting caspase cleaved tau is aspartic acid 421. In another embodiment, the epitope for antibodies targeting caspase cleaved tau may be the C-terminus after glutamic residue Glu391. In yet another embodiment, the epitope for antibodies targeting caspase cleaved tau may be at the N-terminus at aspartic acid residue 13. In another embodiment, the antibody may be TauC3.

In some embodiments, the antibodies encoded by the viral genomes of the present disclosure may target any of the antigenic regions or epitopes described in United States Patent Publication US20160031978, the contents of which are herein incorporated by reference in their entirety. In some embodiments, the antibody may bind to tau N-terminal residues associated with the PP1/GSK3 signaling cascade. In some embodiments, the antibody may be TNT1.

In some embodiments, the antibodies encoded by the viral genomes of the present disclosure may be any of those described in d'Abramo, C et al., 2015. PLOS One 10(8):e0135774, the contents of which are herein incorporated by reference in their entirety. In some embodiments, the antibody may be CP13 (pS202), or a fragment or variant thereof. In another embodiment, the antibody may be RZ3 (pT231), or a fragment or variant thereof. In another embodiment, the antibody may be PG5 (pS409), or a fragment or variant thereof.

Anti-tau antibodies or fragments thereof encoded by the viral genomes of the present disclosure may target tau in any antigenic form. As non-limiting examples, antigenic tau may be an unphosphorylated or unmodified tau protein, a phosphorylated or otherwise post-translationally modified tau protein (0-GlnAcylated, or nitrosylated), an oligomeric species of tau protein, a soluble species of tau protein, an insoluble species of tau protein, a conformationally abnormal species of tau protein, a neuropathological form of tau protein and/or a neurofibrillary tangle or a precursor thereof.

Anti-tau antibodies or fragments thereof encoded by the viral genomes, may target any antigenic region or epitope along the full length of any of the six human tau protein isoforms. As non-limiting examples, the targeted antigenic peptides of the tau protein may be any of the following phosphorylated sites pT50, pS396, pS396-pS404, pS404, pS396-pS404-pS422, pS409, pS413, pS422, pS198, pS199, pS199-pS202, pS202, pT205, pT212, pS214, pT212-pS214, pT181, pT231, cis-pT231, pS235, pS238, pT245, pS262, pY310, pY394, pS324, pS356, pTau¹⁷⁷⁻¹⁸⁷, pY18, pS610, pS622, nitrosylated tau (nY18, nY29), methylated tau (di-meK281, dimeK311), O-GlnAcylated tau at S400, any of the following acetylated sites acK174, acK274, acK280, acK281 and/or any combination thereof. Acetylated tau proteins and associated antigenic peptides are described in Min et al., 2010, Neuron., 67, 953-966, Min et al., 2015, Nature Medicine., 10, 1154-1162, Cohen et al., 2011, Nature Communications., 2, 252, Gorsky et al., 2016, Scientific Report., 6, 22685, Tracy et al., 2016, Neuron., 90, 245-260, the contents of each of which are herein incorporated by reference in their entirety. Phosphorylated tau proteins and associated antigenic peptides are described in Asuni et al., 2007. J Neurosci., 27, 9115-9129. Boutajangout et al., 2010. J Neurosci., 30, 16559-16566, Boutajangout et al., 2011, J Neurochem., 118, 658-667. Chai et al., 2011, J Biol Chem., 286, 34457-34467, Gu et al., 2011, J Biol Chem., 288, 33081-33095, Sankaranarayanan et al., 2015, PloS One, 10, e0125614, Ittner et al., 2015, J Neurochem., 132, 135-145, D'Abramo et al., 2016, Neurobiol Aging., 37, 58-65, Collin et al., 2014, Brain., 137, 2834-2846, Kondo et al., 2015, Nature., 523, 431-436, the contents of each of which are herein incorporated by reference in their entirety.

In some embodiments, the antibody encoded by the viral genomes of the present disclosure may be a pS409 targeting antibody as described in Lee et al., 2016, Cell Reports, 16, 1690-1700, or International Patent Publication WO2013151762, the contents of each of which am herein incorporated by reference in their entirety. In some embodiments, this antibody may be RG6100 or R071057 or variants or fragments thereof.

In some embodiments, the antibody encoded by the viral genomes of the present disclosure may be a pS413 targeting antibody as described in Umeda et al., 2015, Ann Clin Trans Neurol., 2(3), 241-255 or International Patent Publication WO2013180238, the contents of each of which are herein incorporated by reference in their entirety. In some embodiments, the antibody is Ta1505 or variants or fragments thereof.

In some embodiments, the antibody encoded by the viral genomes of the present disclosure may target a tau epitope with amino acid residues 210-275, more specifically pS238 and/or pT245, as described in International Publication WO2011053565, the contents of which are herein incorporated by reference in their entirety.

In some embodiments, the CDRs of an antibody encoded by the viral genomes of the present disclosure may be any of those listed in or incorporated in the antibody sequences of Table 3. In some embodiments, the CDRs may be any of those described in International Publication WO2015122922, the contents of which are herein incorporated by reference in their entirety. In some embodiments, a CDR may be any of those chosen from the group of SEQ ID NO: 41, 49, or 57 of WO2015122922. Further a CDR of an antibody encoded by the viral genomes of the present disclosure may have 50%, 60%, 70%, 80%, 90%, or 95% identity to SEQ ID NO: 41, 49, or 57 of WO2015122922.

In some embodiments, the antibodies encoded by the viral genomes of the present disclosure may be any of those described in International Publication WO2016097315, the contents of which are herein incorporated by reference in their entirety. In some embodiments, the antibody may have an amino acid sequence as shown by SEQ ID NO: 2, 11, 20, 29, 38, 47, 56, 65, 74, 83, 92, 101, 110, 119, 128, 137, 146, 155, 164, 173, 182, 191, 209, 218, 226, or 227 of WO2016097315.

In some embodiments, the antibodies encoded by the viral genomes of the present disclosure may be a multispecific blood brain barrier receptor antibody that also targets tau, as described in International Publication WO2016094566, the contents of which are herein incorporated by reference in their entirety. In some embodiments, the antibody may have a sequence as shown by SEQ ID NO: 1, 2, 17, 18, 33, 34, 49, 50, 65, 66, 81, 82, 9-16, 25-32, 41-48, 57-64, 73-80, 89-96 of WO2016094566.

In some embodiments, the antibodies (or fragments thereof) encoded by the viral genomes of the present disclosure may be any of those taught in U.S. Pat. Nos. 8,778,343 and 9,125,846, International Publications WO2012051498 and WO2011026031, or United States Publication Nos. US20150004169 and US20150322143, the contents of each of which are herein incorporated by reference in their entirety. Such antibodies may include those that bind to oligomeric species of tau. Further, such an antibody may be referred to as TOMA (tau oligomer monoclonal antibody), as described in Castillo-Carranza et at (Castillo-Carranza, D L et al., 2014 J Neurosci 34(12)4260-72) the contents of which are herein incorporated by reference in their entirety. In some embodiments, the antibody that binds oligomeric tau may be TTC-99.

In some embodiments, the antibodies (or fragments thereof) encoded by the viral genomes of the present disclosure may be any of those taught in International Publications WO2014059442, the contents of which are herein incorporated by reference in their entirety. Such antibodies may include those that bind to oligomeric species of tau.

In some embodiments, the antibodies (or fragments thereof) encoded by the viral genomes of the present disclosure may be any of those taught in the International Publications WO2014008404 and WO2016126993, United States Patent Publication US20150183855, Yanamandra, K et al., 2013 Neuron 80(2):402-14 and Yanamandra, K et al 2015 Ann Clin Transl Neurol 2(3):278-88, the contents of each of which are herein incorporated by reference in their entirety. Such antibodies may block tau seeding. Non-limiting examples of antibodies described in these publications include HJ8.1.1, HJ8.1.2, HJ8.2, HJ8.3, HJ8.4, HJ8.5, HJ8.7, HJ8.8, HJ9.1, HJ9.2, HJ9.3, HJ9.4, HJ9.5, and variants thereof. Non-limiting examples of targeted epitopes of tau may include amino acids 22-34, 385-391, 405-411, 3-6, 118-122, 386-401, 7-13, and/or 272-281 of human tau.

In some embodiments, the antibodies (or fragments thereof) encoded by the viral genomes of the present disclosure may be any of those taught in the International Publications WO2002062851, the contents of which are herein incorporated by reference in their entirety.

In some embodiments, the antibodies (or fragments thereof) encoded by the viral genomes of the present disclosure may be as described in Bright, J et al., 2015 Neurobiol of Aging 36:693-709; Pedersen, J T and Sigurdsson E M, 2015 Trends Mol Med 21(6):394-402; Levites, Y et al 2015 J Neurosci 35(16)6265-76; Jicha et al 1999 J Neurosci 19(17):7486-94; Reyes J F et al., 2012 Acta Neuropathol 123(1):119-32; Reynolds M R, et al., 2006 J Neurosci 26(42):10636-45; Gamblin, T C et al 2003 PNAS 100(17):10032-7; Castillo-Carranza, D L et al., 2014 J Neurosci 34(12)4260-72; Walls, K C et al., 2014 Neurosci Lett 575:96-100; Yanamandra, K et al., 2013 Neuron 80(2):402-14; Yanamandra, K et al 2015 Ann Clin Transl Neurol 2(3):278-88: Allen B. et al., 2002 J Neurosci 22(21):9340-51: Gotz, J et al., 2010 Biochem Biophys Acta 1802(10):860-71; Hasegawa, M et al 1996 FEBS Lett 384:25-30; Carmel, G et al 1996 J Biol Chem 271(51):32780-32795; Jicha, G A et al, 1997 J Neurosci Res 48(2):128-132; Jicha, G A et al., 1997 J Neurochem 69(5):2087-95; the contents of each of which are herein incorporated by reference in their entirety.

Anti-tau antibodies or fragments thereof encoded by the viral genomes of the present disclosure may be any commercially available anti-tau antibody known in the art or developed by a person with skill in the art. Non-limiting examples of commercially available anti-tau antibodies include EPR2396(2) (pThr⁵⁰; Abeam, Cambridge, Mass.), 5H911 (pThr¹⁸³; ThermoFisher, Waltham, Mass.), M7004D06 (pThr¹⁸¹; BioLegend, San Diego, Calif.), 1E7 (pThr¹⁸¹; EMD Millipore, Billerica, Mass.), EPR2400 (pSer¹⁹⁸; Abcam, Cambridge, Mass.), EPR2401Y (pSer¹⁹⁹; Abcam, Cambridge, Mass.), 2H23L4 (pSer¹⁹⁹; ThermoFisher, Waltham, Mass.), EPR2402 (pSer²⁰²; Abcam, Cambridge, Mass.), 10F8 (pSer²⁰²; Abcam, Cambridge, Mass.), EPR2403(2) (pThr²⁰⁵; Abcam, Cambridge, Mass.), EPR1884(2) (pSer²¹⁴; Abcam, Cambridge, Mass.), EPR2488 (pThr²³¹; Abcam, Cambridge, Mass.), 1H6L6 (pThr²³¹; ThermoFisher, Waltham, Mass.), 3G3 (pThr²³¹, pSer²³⁵; Abeam, Cambridge, Mass.), EPR2452 (pSer²³⁵; Abcam, Cambridge, Mass.), 12G10 (pSer²³⁹; Abcam, Cambridge, Mass.), EPR2454 (pSer²⁶²; Abcam, Cambridge, Mass.), EPR2457(2) (pSer³²⁴; Abcam, Cambridge, Mass.), EPR2603 (pSer³⁵⁶; Abcam, Cambridge, Mass.), EPR2731 (pSer³⁹⁶; Abcam, Cambridge, Mass.), EPR2605 (pSer⁴⁰⁴; Abcam, Cambridge, Mass.), EPR2866 (pSer⁴²²; Abcam, Cambridge, Mass.), 1A4 (pTau¹⁷⁷⁻¹⁸⁷; Origene, Rockville, Md.), 7G9 (pTau¹⁷⁷⁻⁸⁷; Origene, Rockville, Md.), 9B4 (pTau¹⁷⁷⁻¹⁸⁷; Origene, Rockville, Md.), 2A4 (pTau¹⁷⁷⁻¹⁸⁷; Origene, Rockville, Md.), 9G3 (pTyr¹⁸; NovusBio, Littleton, Colo.), EPR2455(2) (pSer⁶¹⁰; Abcam, Cambridge, Mass.), EP2456Y (pSer⁶²²; Abcam, Cambridge, Mass.; EMD Millipore, Billerica, Mass.), SMI 51 (PHF Tau⁹⁵⁻¹⁰⁸; BioLegend, San Diego, Calif.), TOMA-1 (Oligomeric Tau; EMD Millipore, Billerica, Mass.), Tau-nY18 (nTyr¹⁸; Origene, Rockville, Md.; BioLegend, San Diego, Calif.; EMD Millipore, Billerica, Mass.), Tau-nY29 (nTyr²⁹; BioLegend, San Diego, Calif.; EMD Millipore, Billerica, Mass.; Abcam, Cambridge, Mass.), 1C9.G6 (di-methyl-Lys²⁸¹; BioLegend, San Diego, Calif.), 7G5.F4 (di-methyl-Lys³¹¹; BioLegend, San Diego, Calif.), TNT-1 (Tau²⁻¹⁸; EMD Millipore, Billerica, Mass.), TNT-2 (Tau²⁻¹⁸; EMD Millipore. Billerica, Mass.). 7B8 (Tau⁵⁻¹²; Abcam, Cambridge, Mass.), Tau-13 (Tau²⁰⁻³⁵; BioLegend, San Diego, Calif.), 1-100 (Tau¹⁻¹⁰⁰; BioLegend, San Diego, Calif.), 2G9.F10 (Tau¹⁵⁷⁻¹⁶⁸; BioLegend, San Diego, Calif.; Origene, Rockville, Md.), 39E10 (Tau¹⁸⁹⁻¹⁹⁵; BioLegend, San Diego, Calif.; Origene, Rockville, Md.), 77E9 (Tau¹⁸⁵⁻¹⁹⁵; BioLegend, San Diego, Calif.; Origene, Rockville, Md.), AT8 (pSer²⁰², pThr²⁰⁵; ThermoFisher, Waltham, Mass.), AT100 (pThr²²¹, pSer²¹⁴; ThermoFisher, Waltham, Mass.), PHF-6 (pThr²³¹; NovusBio, Littleton, Colo.; EMD Millipore, Billerica, Mass.; BioLegend, San Diego, Calif.; ThermoFisher, Waltham, Mass.), AT180 (pThr²³¹; ThermoFisher, Waltham, Mass.), AT270 (pThr¹⁸¹; ThermoFisher, Waltham, Mass.), PHF-13 (pSer³⁹⁶; ThermoFisher, Waltham, Mass.; BioLegend, San Diego, Calif.), TauC3 (Asp⁴²¹; BioLegend, San Diego. Calif.; EMD Millipore, Billerica, Mass.; ThermoFisher, Waltham, Mass.), Tau12 (Tau⁶⁻¹⁸; BioLegend, San Diego, Calif.; EMD Millipore, Billerica, Mass.), Tau5 (Tau²¹⁰⁻²⁴¹; BioLegend, San Diego, Calif.; EMD Millipore, Billerica, Mass.; Abcam, Cambridge Mass.; ThermoFisher, Waltham, Mass.), HT7 (Tau¹⁵⁹⁻¹⁶³; ThermoFisher, Waltham, Mass.), 77G7 (Tau³¹⁶⁻³⁵⁵; BioLegend, San Diego, Calif.), Tau46 (Tau⁴⁰⁴⁻⁴⁴¹; BioLegend, San Diego, Calif.; NovusBio, Littleton, Colo.; Abcam, Cambridge, Mass.), UMAB239 (Tau⁶²³⁻⁷⁵⁸; Origene, Rockville, Md.), OTI16G3 (Tau⁶²³⁻⁷⁵⁸; Origene, Rockville, Md.), OTI13E11 (Tau⁶²³⁻⁸⁰⁰; Origene, Rockville, Md.), OTI13B5 (Tau⁶²³⁻⁷⁵⁸; Origene, Rockville, Md.), E178 (Tau⁷⁰⁰⁻⁸⁰⁰; Abcam, Cambridge, Mass.), SP70 (N-terminal Tau; Origene, Rockville, Md.; NovusBio, Littleton, Colo.; ThermoFisher, Waltham, Mass.; Abcam, Cambridge, Mass.), C45 (N-terminal Tau; Origene, Rockville, Md.), Tau7 (C-terminal Tau; EMD Millipore, Billerica, Mass.), S.125.0 (C-terminal Tau; ThermoFisher, Waltham, Mass.), 8E6/C11 (Three-repeat Tau²⁰⁹⁻²²⁴; EMD Millipore, Billerica, Mass.), 1E1/A6 (Four-repeat Tau²⁷⁵⁻²⁹¹; EMD Millipore, Billerica, Mass.), 7D12.1 (Four-repeat Tau²⁷⁵⁻²⁹¹; EMD Millipore. Billerica, Mass.), 5C7 (Four-repeat Tau²⁶⁷⁻²⁷⁸; BioLegend, San Diego, Calif.; Origene, Rockville, Md.), 5F9 (Four-repeat Tau²⁷⁵⁻²⁹¹; BioLegend, San Diego, Calif.; Origene, Rockville, Md.), 3H6.H7 (0N Tau³⁹⁻⁵⁰; BioLegend, San Diego, Calif.; Origene, Rockville, Md.), 4H5.B9 (1N Tau⁶⁸⁻⁷⁹; BioLegend, San Diego, Calif.; Origene, Rockville, Md.), 71C11 (2N Tau; BioLegend, San Diego, Calif.), PC1C6 (unphosphorylated tau; EMD Millipore, Billerica, Mass.), Tau2 (BioLegend, San Diego, Calif.; Origene, Rockville, Md.; EMD Millipore, Billerica, Mass.), 2E9 (Origene, Rockville, Md.; NovusBio, Littleton, Colo.), 4F1 (Origene, Rockville, Md.; NovusBio, Littleton, Colo.), 5B10 (NovusBio, Littleton, Colo.); 5E2 (EMD Millipore, Billerica, Mass.), Tau-93 (Origene, Rockville, Md.), T14 (ThermoFisher, Waltham, Mass.), T46 (ThermoFisher, Waltham, Mass.), BT2 (ThermoFisher, Waltham, Mass.) and/or variants or derivates thereof.

In some embodiments, the antibodies encoded by the viral genomes of the present disclosure may be multispecific antibodies for transferrin receptor and a brain antigen, wherein the brain antigen may be tau, as described in International Publication WO2016081643, the contents of which are herein incorporated by reference in their entirety. In some embodiments, the antibody may have a sequence as given by SEQ ID NO: 160 or 161 of WO2016081643.

In some embodiments, the antibodies encoded by the viral genomes of the present disclosure are any of those described in U.S. Pat. Nos. 8,871,447, 8,420,613, International Publication No. WO2014193935, WO2010011999, or in United States Publication Nos. US20110250217, US20110020237, US20100316590, or US20120225864, the contents of each of which are herein incorporated by reference in their entirety. In some embodiments, the antibody recognizes a misfolded, amyloidogenic or aggregating protein.

In some embodiments, the viral genome of the AAV particle of the present disclosure encodes anti-tau antibody PT3, or a fragment or variant thereof.

In some embodiments, the viral genome of the AAV particle of the present disclosure encodes anti-tau antibody AT8, or a fragment or variant thereof.

In some embodiments, the viral genome of the AAV particle of the present disclosure encodes anti-tau antibody IPN002, or a fragment or variant thereof.

In some embodiments, the viral genome of the AAV particle of the present disclosure encodes anti-tau antibody MC1, or a fragment or variant thereof.

In some embodiments, the viral genome of the AAV particle of the present disclosure encodes anti-tau antibody PHF1, or a fragment or variant thereof.

In some embodiments, the viral genome of the AAV particle of the present disclosure encodes anti-tau antibody CP13, or a fragment or variant thereof.

In some embodiments, the viral genome of the AAV particle of the present disclosure encodes anti-tau antibody C10.2, or a fragment or variant thereof.

In some embodiments, the viral genome of the AAV particle of the present disclosure encodes anti-tau antibody PHF-13, or a fragment or variant thereof.

In some embodiments, the viral genome of the AAV particle of the present disclosure encodes anti-tau antibody PHF-6, or a fragment or variant thereof.

The Nature of the Polypeptides and Variants

Antibodies encoded by payload regions of the viral genomes may be translated as a whole polypeptide, a plurality of polypeptides or fragments of polypeptides, which independently may be encoded by one or more nucleic acids, fragments of nucleic acids or variants of any of the aforementioned. As used herein, “polypeptide” means a polymer of amino acid residues (natural or unnatural) linked together most often by peptide bonds. The term, as used herein, refers to proteins, polypeptides, and peptides of any size, structure, or function. In some instances, the polypeptide encoded is smaller than about 50 amino acids and the polypeptide is then termed a peptide. If the polypeptide is a peptide, it will be at least about 2, 3, 4, or at least 5 amino acid residues long. Thus, polypeptides include gene products, naturally occurring polypeptides, synthetic polypeptides, homologs, orthologs, paralogs, fragments and other equivalents, variants, and analogs of the foregoing. A polypeptide may be a single molecule or may be a multi-molecular complex such as a dimer, trimer or tetramer. They may also comprise single chain or multichain polypeptides and may be associated or linked. The term polypeptide may also apply to amino acid polymers in which one or more amino acid residues are an artificial chemical analogue of a corresponding naturally occurring amino acid.

The term “polypeptide variant” refers to molecules which differ in their amino acid sequence from a native or reference sequence. The amino acid sequence variants may possess substitutions, deletions, and/or insertions at certain positions within the amino acid sequence, as compared to a native or reference sequence. Ordinarily, variants will possess at least about 50% identity (homology) to a native or reference sequence, and preferably, they will be at least about 80%, more preferably at least about 90% identical (homologous) to a native or reference sequence.

In some embodiments “variant mimics” are provided. As used herein, the term “variant mimic” is one which contains one or more amino acids which would mimic an activated sequence. For example, glutamate may serve as a mimic for phosphoro-threonine and/or phosphoro-serine. Alternatively, variant mimics may result in deactivation or in an inactivated product containing the mimic, e.g., phenylalanine may act as an inactivating substitution for tyrosine; or alanine may act as an inactivating substitution for serine.

The term “amino acid sequence variant” refers to molecules with some differences in their amino acid sequences as compared to a native or starting sequence. The amino acid sequence variants may possess substitutions, deletions, and/or insertions at certain positions within the amino acid sequence. “Native” or “starting” sequence should not be confused with a wild type sequence. As used herein, a native or starting sequence is a relative term referring to an original molecule against which a comparison may be made. “Native” or “starting” sequences or molecules may represent the wild-type (that sequence found in nature) but do not have to be the wild-type sequence.

Ordinarily, variants will possess at least about 70% homology to a native sequence, and preferably, they will be at least about 80/6, more preferably at least about 90% homologous to a native sequence. “Homology” as it applies to amino acid sequences is defined as the percentage of residues in the candidate amino acid sequence that are identical with the residues in the amino acid sequence of a second sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent homology. Methods and computer programs for the alignment are well known in the art. It is understood that homology depends on a calculation of percent identity but may differ in value due to gaps and penalties introduced in the calculation.

By “homologs” as it applies to amino acid sequences is meant the corresponding sequence of other species having substantial identity to a second sequence of a second species.

“Analogs” is meant to include polypeptide variants which differ by one or more amino acid alterations, e.g., substitutions, additions, or deletions of amino acid residues that still maintain the properties of the parent polypeptide.

Sequence tags or amino acids, such as one or more lysines, can be added to the peptide sequences (e.g., at the N-terminal or C-terminal ends). Sequence tags can be used for peptide purification or localization. Lysines can be used to increase peptide solubility or to allow for biotinylation. Alternatively, amino acid residues located at the carboxy and amino terminal regions of the amino acid sequence of a peptide or protein may optionally be deleted providing for truncated sequences. Certain amino acids (e.g., C-terminal or N-terminal residues) may alternatively be deleted depending on the use of the sequence, as for example, expression of the sequence as part of a larger sequence which is soluble, or linked to a solid support.

“Substitutional variants” when referring to proteins are those that have at least one amino acid residue in a native or starting sequence removed and a different amino acid inserted in its place at the same position. The substitutions may be single, where only one amino acid in the molecule has been substituted, or they may be multiple, where two or more amino acids have been substituted in the same molecule.

As used herein the term “conservative amino acid substitution” refers to the substitution of an amino acid that is normally present in the sequence with a different amino acid of similar size, charge, or polarity. Examples of conservative substitutions include the substitution of a non-polar (hydrophobic) residue such as isoleucine, valine, and leucine for another non-polar residue. Likewise, examples of conservative substitutions include the substitution of one polar (hydrophilic) residue for another such as between arginine and lysine, between glutamine and asparagine, and between glycine and serine. Additionally, the substitution of a basic residue such as lysine, arginine, or histidine for another, or the substitution of one acidic residue such as aspartic acid or glutamic acid for another acidic residue are additional examples of conservative substitutions. Examples of non-conservative substitutions include the substitution of a non-polar (hydrophobic) amino acid residue such as isoleucine, valine, leucine, alanine, methionine for a polar (hydrophilic) residue such as cysteine, glutamine, glutamic acid or lysine and/or a polar residue for a non-polar residue.

“Insertional variants” when referring to proteins are those with one or more amino acids inserted immediately adjacent to an amino acid at a particular position in a native or starting sequence. “Immediately adjacent” to an amino acid means connected to either the alpha-carboxy or alpha-amino functional group of the amino acid.

“Deletional variants” when referring to proteins, are those with one or more amino acids in the native or starting amino acid sequence removed. Ordinarily, deletional variants will have one or more amino acids deleted in a particular region of the molecule.

As used herein, the term “derivative” is used synonymously with the term “variant” and refers to a molecule that has been modified or changed in any way relative to a reference molecule or starting molecule. In some embodiments, derivatives include native or starting proteins that have been modified with an organic proteinaceous or non-proteinaceous derivatizing agent, and post-translational modifications. Covalent modifications are traditionally introduced by reacting targeted amino acid residues of the protein with an organic derivatizing agent that is capable of reacting with selected side-chains or terminal residues, or by harnessing mechanisms of post-translational modifications that function in selected recombinant host cells. The resultant covalent derivatives are useful in programs directed at identifying residues important for biological activity, for immunoassays, or for the preparation of anti-protein antibodies for immunoaffinity purification of the recombinant glycoprotein. Such modifications are within the ordinary skill in the art and are performed without undue experimentation.

Certain post-translational modifications are the result of the action of recombinant host cells on the expressed polypeptide. Glutaminyl and asparaginyl residues are frequently post-translationally deamidated to the corresponding glutamyl and aspartyl residues. Alternatively, these residues are deamidated under mildly acidic conditions. Either form of these residues may be present in the proteins used in accordance with the present disclosure.

Other post-translational modifications include hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or threonyl residues, methylation of the alpha-amino groups of lysine, arginine, and histidine side chains (T. E. Creighton, Proteins: Structure and Molecular Properties, W.H. Freeman & Co., San Francisco, pp. 79-86 (1983)).

“Features” when referring to proteins are defined as distinct amino acid sequence-based components of a molecule. Features of the proteins of the present disclosure include surface manifestations, local conformational shape, folds, loops, half-loops, domains, half-domains, sites, termini or any combination thereof.

As used herein when referring to proteins the term “surface manifestation” refers to a polypeptide-based component of a protein appearing on an outermost surface.

As used herein when referring to proteins the term “local conformational shape” means a polypeptide based structural manifestation of a protein which is located within a definable space of the protein.

As used herein when referring to proteins the term “fold” means the resultant conformation of an amino acid sequence upon energy minimization. A fold may occur at the secondary or tertiary level of the folding process. Examples of secondary level folds include beta sheets and alpha helices. Examples of tertiary folds include domains and regions formed due to aggregation or separation of energetic forces. Regions formed in this way include hydrophobic and hydrophilic pockets, and the like.

As used herein the term “turn” as it relates to protein conformation means a bend which alters the direction of the backbone of a peptide or polypeptide and may involve one, two, three or more amino acid residues.

As used herein when referring to proteins the term “loop” refers to a structural feature of a peptide or polypeptide which reverses the direction of the backbone of a peptide or polypeptide and comprises four or more amino acid residues. Oliva et al. have identified at least 5 classes of protein loops (J. Mol Biol 266 (4): 814-830: 1997).

As used herein when referring to proteins the term “half-loop” refers to a portion of an identified loop having at least half the number of amino acid residues as the loop from which it is derived. It is understood that loops may not always contain an even number of amino acid residues. Therefore, in those cases where a loop contains or is identified to comprise an odd number of amino acids, a half-loop of the odd-numbered loop will comprise the whole number portion or next whole number portion of the loop (number of amino acids of the loop/2+/−0.5 amino acids). For example, a loop identified as a 7-amino acid loop could produce half-loops of 3 amino acids or 4 amino acids (7/2=3.5+/−0.5 being 3 or 4).

As used herein when referring to proteins the term “domain” refers to a motif of a polypeptide having one or more identifiable structural or functional characteristics or properties (e.g., binding capacity, serving as a site for protein-protein interactions).

As used herein when referring to proteins the term “half-domain” means portion of an identified domain having at least half the number of amino acid residues as the domain from which it is derived. It is understood that domains may not always contain an even number of amino acid residues. Therefore, in those cases where a domain contains or is identified to comprise an odd number of amino acids, a half-domain of the odd-numbered domain will comprise the whole number portion or next whole number portion of the domain (number of amino acids of the domain/2+/−0.5 amino acids). For example, a domain identified as a 7-amino acid domain could produce half-domains of 3 amino acids or 4 amino acids (7/2=3.5+/−0.5 being 3 or 4). It is also understood that sub-domains may be identified within domains or half-domains, these subdomains possessing less than all of the structural or functional properties identified in the domains or half domains from which they were derived. It is also understood that the amino acids that comprise any of the domain types herein need not be contiguous along the backbone of the polypeptide (i.e., nonadjacent amino acids may fold structurally to produce a domain, half-domain or subdomain).

As used herein when referring to proteins the terms “site” as it pertains to amino acid-based embodiments is used synonymous with “amino acid residue” and “amino acid side chain”. A site represents a position within a peptide or polypeptide that may be modified, manipulated, altered, derivatized or varied within the polypeptide-based molecules of the present disclosure.

As used herein the terms “termini or terminus” when referring to proteins refers to an extremity of a peptide or polypeptide. Such extremity is not limited only to the first or final site of the peptide or polypeptide but may include additional amino acids in the terminal regions. The polypeptide-based molecules of the present disclosure may be characterized as having both an N-terminus (terminated by an amino acid with a free amino group (NH2)) and a C-terminus (terminated by an amino acid with a free carboxyl group (COOH)). Proteins are in some cases made up of multiple polypeptide chains brought together by disulfide bonds or by non-covalent forces (multimers, oligomers). These sorts of proteins will have multiple N- and C-termini. Alternatively, the termini of the polypeptides may be modified such that they begin or end, as the case may be, with a non-polypeptide-based moiety such as an organic conjugate.

Once any of the features have been identified or defined as a component of a molecule, any of several manipulations and/or modifications of these features may be performed by moving, swapping, inverting, deleting, randomizing, or duplicating. Furthermore, it is understood that manipulation of features may result in the same outcome as a modification to the molecules. For example, a manipulation which involves deleting a domain would result in the alteration of the length of a molecule just as modification of a nucleic acid to encode less than a full-length molecule would.

Modifications and manipulations can be accomplished by methods known in the art such as site directed mutagenesis. The resulting modified molecules may then be tested for activity using in vitro or in vivo assays such as those described herein or any other suitable screening assay known in the art.

AAV Production

The present disclosure provides methods for the generation of parvoviral particles, e.g. AAV particles, by viral genome replication in a viral replication cell.

In accordance with the disclosure, the viral genome comprising a payload region encoding an antibody, an antibody-based composition or fragment thereof, will be incorporated into the AAV particle produced in the viral replication cell. Methods of making AAV particles are well known in the art and are described in e.g., U.S. Pat. Nos. 6,204,059, 5,756,283, 6,258,595, 6,261,551, 6,270,996, 6,281,010, 6,365,394, 6,475,769, 6,482,634, 6,485,966, 6,943,019, 6,953,690, 7,022,519, 7,238,526, 7,291,498 and 7,491,508, 5,064,764, 6,194,191, 6,566,118, 8,137,948; or International Publication Nos. WO1996039530, WO1998010088. WO1999014354, WO1999015685, WO1999047691, WO2000055342. WO2000075353, and WO2001023597; Methods In Molecular Biology, ed. Richard. Humana Press, N J (1995); O'Reilly et al., Baculovirus Expression Vectors, A Laboratory Manual, Oxford Univ. Press (1994); Samulski et al., J. Vir. 63:3822-8 (1989); Kajigaya et al., Proc. Nat'l. Acad. Sci. USA 88: 4646-50 (1991); Ruffing et al., J. Vir. 66:6922-30 (1992); Kimbauer et al., Vir., 219:37-44 (1996); Zhao et al., Vir. 272:382-93 (2000); the contents of each of which are herein incorporated by reference in their entirety. In some embodiments, the AAV particles are made using the methods described in WO2015191508, the contents of which are herein incorporated by reference in their entirety.

Viral replication cells commonly used for production of recombinant AAV viral vectors include but are not limited to 293 cells, COS cells, HeLa cells, KB cells, and other mammalian cell lines as described in U.S. Pat. Nos. U.S. Pat. Nos. 6,156,303, 5,387,484, 5,741,683, 5,691,176, and 5,688,676; U.S. patent publication No. 2002/0081721, and International Patent Publication Nos. WO 00/47757, WO 00/24916, and WO 96/17947, the contents of each of which are herein incorporated by reference in their entireties.

In some embodiments, the AAV particles of the present disclosure may be produced in insect cells (e.g., Sf9 cells).

In some embodiments, the AAV particles of the present disclosure may be produced using triple transfection.

In some embodiments, the AAV particles of the present disclosure may be produced in mammalian cells.

In some embodiments, the AAV particles of the present disclosure may be produced by triple transfection in mammalian cells.

In some embodiments, the AAV particles of the present disclosure may be produced by triple transfection in HEK293 cells.

The present disclosure provides a method for producing an AAV particle comprising the steps of: 1) co-transfecting competent bacterial cells with a bacmid vector and either a viral construct vector and/or AAV payload construct vector, 2) isolating the resultant viral construct expression vector and AAV payload construct expression vector and separately transfecting viral replication cells, 3) isolating and purifying resultant payload and viral construct particles comprising viral construct expression vector or AAV payload construct expression vector, 4) co-infecting a viral replication cell with both the AAV payload and viral construct particles comprising viral construct expression vector or AAV payload construct expression vector, 5) harvesting and purifying the viral particle comprising a parvoviral genome.

In some embodiments, the present disclosure provides a method for producing an AAV particle comprising the steps of 1) simultaneously co-transfecting mammalian cells, such as, but not limited to HEK293 cells, with a payload region, a construct expressing rep and cap genes and a helper construct, 2) harvesting and purifying the AAV particle comprising a viral genome.

In some embodiments, the viral construct vector(s) used for AAV production may contain a nucleotide sequence encoding the AAV capsid proteins where the initiation codon of the AAV VP1 capsid protein is a non-ATG, i.e., a suboptimal initiation codon, allowing the expression of a modified ratio of the viral capsid proteins in the production system, to provide improved infectivity of the host cell. In a non-limiting example, a viral construct vector may contain a nucleic acid construct comprising a nucleotide sequence encoding AAV VP1, VP2, and VP3 capsid proteins, wherein the initiation codon for translation of the AAV VP1 capsid protein is CTG, TTG, or GTG, as described in U.S. Pat. No. 8,163,543, the contents of which are herein incorporated by reference in its entirety.

In some embodiments, the viral construct vector(s) used for AAV production may contain a nucleotide sequence encoding the AAV rep proteins where the initiation codon of the AAV rep protein or proteins is a non-ATG. In some embodiments, a single coding sequence is used for the Rep78 and Rep52 proteins, wherein initiation codon for translation of the Rep78 protein is a suboptimal initiation codon, selected from the group consisting of ACG, TTG, CTG and GTG, that effects partial exon skipping upon expression in insect cells, as described in U.S. Pat. No. 8,512,981, the contents of which is herein incorporated by reference in its entirety, for example to promote less abundant expression of Rep78 as compared to Rep52, which may be advantageous in that it promotes high vector yields.

In some embodiments, the viral genome of the AAV particle optionally encodes a selectable marker. The selectable marker may comprise a cell-surface marker, such as any protein expressed on the surface of the cell including, but not limited to receptors, CD markers, lectins, integrins, or truncated versions thereof.

In some embodiments, selectable marker reporter genes are selected from those described in International Application No. WO 96/23810; Heim et al., Current Biology 2:178-182 (1996); Heim et al., Proc. Natl. Acad. Sci. USA (1995); or Heim et al., Science 373:663-664 (1995); WO 96/30540, the contents of each of which are incorporated herein by reference in their entireties).

The AAV viral genomes encoding an anti-tau antibody payload described herein may be useful in the fields of human disease, veterinary applications and a variety of in vivo and in vitro settings. The AAV particles of the present disclosure may be useful in the field of medicine for the treatment, prophylaxis, palliation or amelioration of neurological diseases and/or disorders. In some embodiments, the AAV particles are used for the prevention and/or treatment of a tauopathy.

Various embodiments herein provide a pharmaceutical composition comprising the AAV particles described herein and a pharmaceutically acceptable excipient.

Various embodiments herein provide a method of treating a subject in need thereof comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition described herein.

Certain embodiments of the method provide that the subject is treated by a route of administration of the pharmaceutical composition selected from the group consisting of intravenous, intracerebroventricular, intraparenchymal, intrathecal, subpial and intramuscular, or a combination thereof. Certain embodiments of the method provide that the subject is treated for a tauopathy and/or other neurological disorder. In one aspect of the method, a pathological feature of the tauopathy or other neurological disorder is alleviated and/or the progression of the tauopathy or other neurological disorder is halted, slowed, ameliorated or reversed.

Various embodiments herein describe a method of decreasing the level of soluble tau in the central nervous system of a subject in need thereof comprising administering to said subject an effective amount of the pharmaceutical composition described herein.

Also described herein are compositions, methods, processes, kits and devices for the design, preparation, manufacture and/or formulation of AAV particles. In some embodiments, payloads, such as but not limited to anti-tau antibodies, may be encoded by payload constructs or contained within plasmids or vectors or recombinant adeno-associated viruses (AAVs).

The present disclosure also provides administration and/or delivery methods for vectors and viral particles, e.g., AAV particles, for the treatment or amelioration of neurological disease, such as, but not limited to tauopathy.

AAV Particles Comprising Anti-Tau Antibody Payloads

In some embodiments, the AAV particle comprises a viral genome with a payload region comprising one or more anti-tau antibody polynucleotide sequences. In such an embodiment, a viral genome encoding more than one polypeptide may be replicated and packaged into a viral particle. A target cell transduced with a viral particle comprising one or more anti-tau antibody polynucleotides may express the encoded antibody or antibodies in a single cell.

In some embodiments, the AAV particles are useful in the field of medicine for the treatment, prophylaxis, palliation or amelioration of neurological diseases and/or disorders.

Non-limiting examples of ITR to ITR sequences of AAV particles comprising a viral genome with a payload region comprising an anti-tau antibody polynucleotide sequence are described in Table 4-6.

TABLE 4 ITR to ITR Sequences of AAV particles comprising anti-tau antibody polynucleotide sequences ITR to ITR Sequence ITR to ITR Construct Name Length (nt) SEQ ID NO TAU_ITR1 4450 1990 TAU_ITR2 4471 1991 TAU_ITR3 3983 1992 TAU_ITR4 3962 1993 TAU_ITR5 4041 1994 TAU_ITR6 4020 1995 TAU_ITR7 3899 1996 TAU_ITR8 3878 1997 TAU_ITR9 4459 1998 TAU_ITR10 4438 1999 TAU_ITR11 3971 2000 TAU_ITR12 4029 2001 TAU_ITR13 4008 2002 TAU_ITR14 3887 2003 TAU_ITR15 3866 2004 TAU_ITR16 3932 2005 TAU_ITR17 3932 2006 TAU_ITR18 3932 2007 TAU_ITR19 3932 2008 TAU_ITR20 3932 2009 TAU_ITR21 3932 2010 TAU_ITR22 3932 2011 TAU_ITR23 3932 2012 TAU_ITR24 3932 2013 TAU_ITR25 3932 2014 TAU_ITR26 4309 2015 TAU_ITR27 4309 2016 TAU_ITR28 4309 2017 TAU_ITR29 4309 2018 TAU_ITR30 4309 2019 TAU_ITR31 4309 2020 TAU_ITR32 4309 2021 TAU_ITR33 4309 2022 TAU_ITR34 4309 2023 TAU_ITR35 4309 2024 TAU_ITR87 3950 2137 TAU_ITR88 3962 2138 TAU_ITR89 4450 2139 TAU_ITR90 4020 2140 TAU_ITR91 3878 2141 TAU_ITR92 3950 2142 TAU_ITR93 4438 2143 TAU_ITR94 4008 2144 TAU_ITR95 3866 2145 TAU_ITR96 3941 2146 TAU_ITR97 4429 2147 TAU_ITR98 3999 2148 TAU_ITR99 3857 2149 TAU_ITR100 4420 2150 TAU_ITR101 3990 2151 TAU_ITR102 3848 2152 TAU_ITR103 3971 2153 TAU_ITR104 4459 2154 TAU_ITR105 4029 2155 TAU_ITR106 3887 2156 TAU_ITR107 3938 2157 TAU_ITR108 4447 2158 TAU_ITR109 4017 2159 TAU_ITR110 3875 2160 TAU_ITR111 3950 2161 TAU_ITR112 4438 2162 TAU_ITR113 4008 2163 TAU_ITR114 3866 2164 TAU_ITR115 3938 2165 TAU_ITR116 4426 2166 TAU_ITR117 3996 2167 TAU_ITR118 3854 2168 TAU_ITR119 3950 2161 TAU_ITR120 4438 2162 TAU_ITR121 3455 2171 TAU_ITR122 3498 2172 TAU_ITR123 3282 2173 TAU_ITR124 3300 2174 TAU_ITR125 3943 2175 TAU_ITR126 3988 2176 TAU_ITR127 3772 2177 TAU_ITR128 3790 2178 TAU_ITR129 3324 2179 TAU_ITR130 3814 2180 TAU_ITR131 2567 2181 TAU_ITR132 2582 2182 TAU_ITR133 2597 2183 TAU_ITR134 2612 2184 TAU_ITR135 2627 2185 TAU_ITR136 2642 2186 TAU_ITR137 3055 2187 TAU_ITR138 3070 2188 TAU_ITR139 3085 2189 TAU_ITR140 3100 2190 TAU_ITR141 3115 2191 TAU_ITR142 3130 2192 TAU_ITR143 3160 2193 TAU_ITR144 2569 2194 TAU_ITR145 2584 2195 TAU_ITR146 2599 2196 TAU_ITR147 2614 2197 TAU_ITR148 2627 2198 TAU_ITR149 2642 2199 TAU_ITR150 3055 2200 TAU_ITR151 3070 2201 TAU_ITR152 3084 2202 TAU_ITR153 3100 2203 TAU_ITR154 3115 2204 TAU_ITR155 3130 2205 TAU_ITR156 3097 2206 TAU_ITR157 3082 2207 TAU_ITR158 3097 2208 TAU_ITR159 3112 2209 TAU_ITR160 3097 2210 TAU_ITR161 3082 2211 TAU_ITR162 3097 2212 TAU_ITR163 3112 2213 TAU_ITR164 2652 2214 TAU_ITR165 2667 2215 TAU_ITR166 2730 2216 TAU_ITR167 2510 2217 TAU_ITR168 2525 2218 TAU_ITR169 2540 2219 TAU_ITR170 3091 2220 TAU_ITR171 3082 2221 TAU_ITR172 3103 2222 TAU_ITR173 3109 2223 TAU_ITR174 3115 2224 TAU_ITR175 3121 2225 TAU_ITR176 3097 2226 TAU_ITR177 3124 2227 TAU_ITR178 3109 2228 TAU_ITR179 3157 2229 TAU_ITR180 3760 2230 TAU_ITR181 3781 2231 TAU_ITR182 3778 2232 TAU_ITR183 3748 2233 TAU_ITR184 3769 2234 TAU_ITR185 3766 2235 TAU_ITR186 3760 2236 TAU_ITR187 3778 2237 TAU_ITR188 3188 2260 TAU_ITR189 3330 2261 TAU_ITR190 3976 2262 TAU_ITR191 3404 2263 TAU_ITR192 3546 2264 TAU_ITR193 3997 2265 TAU_ITR194 3425 2266 TAU_ITR195 3567 2267 TAU_ITR196 3088 2268 TAU_ITR197 3558 2269 TAU_ITR198 3360 2270 TAU_ITR199 3384 2271 TAU_ITR200 2625 2272 TAU_ITR201 2655 2273 TAU_ITR202 2685 2274 TAU_ITR203 2730 2275 TAU_ITR204 2625 2276 TAU_ITR205 2655 2277 TAU_ITR206 2685 2278 TAU_ITR207 3416 2279 TAU_ITR208 3218 2280 TAU_ITR209 3242 2281 TAU_ITR210 2483 2282 TAU_ITR211 2513 2283 TAU_ITR212 2543 2284 TAU_ITR213 2588 2285 TAU_ITR214 2483 2286 TAU_ITR215 2513 2287 TAU_ITR216 2543 2288 TAU_ITR217 3967 2289 TAU_ITR218 3769 2290 TAU_ITR219 3792 2291 TAU_ITR220 3751 2292 TAU_ITR221 3058 2293 TAU_ITR222 3088 2294 TAU_ITR223 3118 2295 TAU_ITR224 3163 2296 TAU_ITR225 3537 2297 TAU_ITR226 3339 2298 TAU_ITR227 3362 2299 TAU_ITR228 3321 2300 TAU_ITR229 2628 2301 TAU_ITR230 2658 2302 TAU_ITR231 2688 2303 TAU_ITR232 2733 2304 TAU_ITR233 3395 2305 TAU_ITR234 3197 2306 TAU_ITR235 3220 2307 TAU_ITR236 3179 2308 TAU_ITR237 2486 2309 TAU_ITR238 2516 2310 TAU_ITR239 2546 2311 TAU_ITR240 2591 2312

TABLE 5 ITR to ITR Sequences of AAV particles comprising anti-tau antibody polynucleotide sequences ITR to ITR Sequence ITR to ITR Construct Name Length (nt) SEQ ID NO TAU_ITR36 4253 2025 TAU_ITR37 4716 2026 TAU_ITR38 4716 2027 TAU_ITR39 4698 2028 TAU_ITR40 4689 2029 TAU_ITR41 4716 2030 TAU_ITR42 4716 2031 TAU_ITR43 4698 2032 TAU_ITR44 4689 2033 TAU_ITR45 4253 2034 TAU_ITR46 2350 2035 TAU_ITR47 2370 2036 TAU_ITR48 2282 2037 TAU_ITR49 2314 2038 TAU_ITR50 2350 2039 TAU_ITR51 2370 2040 TAU_ITR52 2624 2041 TAU_ITR53 3778 2042 TAU_ITR54 2029 2043 TAU_ITR55 2218 2044 TAU_ITR56 3778 2045 TAU_ITR57 2624 2046 TAU_ITR58 2350 2047 TAU_ITR59 2029 2048 TAU_ITR60 2218 2049 TAU_ITR61 4188 2050 TAU_ITR62 3435 2051 TAU_ITR63 4395 2052 TAU_ITR64 3510 2053 TAU_ITR65 4131 2054 TAU_ITR66 3378 2055 TAU_ITR67 4395 2056 TAU_ITR68 3510 2057 TAU_ITR69 4016 2058 TAU_ITR70 4016 2059 TAU_ITR71 3608 2060 TAU_ITR241 3900 2313 TAU_ITR242 4042 2314 TAU_ITR243 3984 2315 TAU_ITR244 4472 2316 TAU_ITR245 2549 2317 TAU_ITR246 2445 2318 TAU_ITR247 2350 2319 TAU_ITR248 4698 2320 TAU_ITR249 4223 2321

TABLE 6 ITR to ITR Sequences of AAV particles comprising anti-tau antibody polynucleotide sequences ITR to ITR Sequence ITR to ITR Construct Name Length (nt) SEQ ID NO TAU_ITR72 3619 2061 TAU_ITR73 3610 2062 TAU_ITR74 3607 2063 TAU_ITR75 4158 2064 TAU_ITR76 3598 2065 TAU_ITR77 3622 2066 TAU_ITR78 3619 2067 TAU_ITR79 3607 2068 TAU_ITR80 4158 2069 TAU_ITR81 3607 2070 TAU_ITR82 3598 2071 TAU_ITR83 3610 2072 TAU_ITR84 3610 2073 TAU_ITR85 3622 2074 TAU_ITR86 3610 2075

In some embodiments, the AAV particle comprises a viral genome which comprises a sequence which has a percent identity to any of SEQ ID NOs: 1990-2075, 2137-2168, 2171-2237, and 2260-2321. The viral genome may have 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identity to any of SEQ ID NOs: 1990-2075, 2137-2168, 2171-2237, and 2260-2321. The viral genome may have 1-10%, 10-20%, 30-40%, 50-60%, 50-70%, 50-80%, 50-90/o. 50-99%, 50-100/6, 60-70%, 60-80%, 60-90%, 60-99%, 60-100%, 70-80%, 70-90%, 70-99%, 70-100%, 80-85%, 80-90%, 80-95%, 80-99%, 80-100%, 90-95%, 90-99%, or 90-100% to any of SEQ ID NOs: 1990-2075, 2137-2168, 2171-2237, and 2260-2321. As a non-limiting example, the viral genome comprises a sequence which has 80% identity to any of SEQ ID NO: 1990-2075, 2137-2168, 2171-2237, and 2260-2321. As another non-limiting example, the viral genome comprises a sequence which has 85% identity to any of SEQ ID NO: 1990-2075, 2137-2168, 2171-2237, and 2260-2321. As another non-limiting example, the viral genome comprises a sequence which has 90% identity to any of SEQ ID NO: 1990-2075, 2137-2168, 2171-2237, and 2260-2321. As another non-limiting example, the viral genome comprises a sequence which has 95% identity to any of SEQ ID NO: 1990-2075, 2137-2168, 2171-2237, and 2260-2321. As another non-limiting example, the viral genome comprises a sequence which has 99% identity to any of SEQ ID NO: 1990-2075, 2137-2168, 2171-2237, and 2260-2321.

In some embodiments, the AAV particles comprising anti-tau antibody polynucleotide sequences which comprise a nucleic acid sequence encoding at least one antibody heavy and/or light chain may be introduced into mammalian cells.

The AAV viral genomes encoding anti-tau antibody polynucleotides described herein may be useful in the fields of human disease, viruses, infections veterinary applications and a variety of in vivo and in vitro settings. In some embodiments, the AAV viral genomes encoding anti-tau antibody polynucleotides are used for the prevention and/or treatment of a tauopathy.

The viral genome of the AAV particles of the present disclosure may comprise any combination of the sequence regions described in Tables 7-14 encapsulated in any of the capsids listed in Table 1 or described herein.

In some embodiments, the AAV particle viral genome may comprise at least one sequence region as described in Tables 7-14. The regions may be located before or after any of the other sequence regions described herein. Viral genomes may further comprise more than one copy of one or more sequence regions as described in Tables 7-14.

In some embodiments, the AAV particle viral genome may comprise at least one inverted terminal repeat (ITR) region. The ITR region(s) may, independently, have a length such as, but not limited to, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, and 175 nucleotides. The length of the ITR region for the viral genome may be 75-80, 75-85, 75-100, 80-85, 80-90, 80-105, 85-90, 85-95, 85-110, 90-95, 90-100, 90-115, 95-100, 95-105, 95-120, 100-105, 100-110, 100-125, 105-110, 105-115, 105-130, 110-115, 110-120, 110-135, 115-120, 115-125, 115-140, 120-125, 120-130, 120-145, 125-130, 125-135, 125-150, 130-135, 130-140, 130-155, 135-140, 135-145, 135-160, 140-145, 140-150, 140-165, 145-150, 145-155, 145-170, 150-155, 150-160, 150-175, 155-160, 155-165, 160-165, 160-170, 165-170, 165-175, and 170-175 nucleotides. As anon-limiting example, the viral genome comprises a 5′ ITR that is about 141 nucleotides in length. As a non-limiting example, the viral genome comprises a 5′ ITR that is about 130 nucleotides in length.

In some embodiments, the AAV particle viral genome comprises at least one 5′ inverted terminal repeat (5′ ITR) sequence region. Non-limiting examples of 5′ ITR sequence regions are described in Table 7.

TABLE 7 Inverted Terminal Repeat (ITR) Sequence Regions Sequence Sequence Region Name Length SEQ ID NO ITR1 130 2076 ITR2 141 2077 ITR3 130 2078 ITR4 141 2079

In some embodiments, the AAV particle viral genome may have an ITR that comprises ITR1. In some embodiments, the AAV particle viral genome may have an ITR that comprises ITR2. In some embodiments, the AAV particle viral genome may have an ITR that comprises ITR3. In some embodiments, the AAV particle viral genome may have an ITR that comprises ITR4.

In some embodiments, the AAV particle viral genome may have two ITRs. As a non-limiting example, the two ITRs are ITR1 and ITR3. As a non-limiting example, the two ITRs are ITR1 and ITR4. As a non-limiting example, the two ITRs are ITR2 and ITR3. As a non-limiting example, the two ITRs are ITR2 and ITR4

In some embodiments, the AAV particle viral genome may comprise at least one promoter sequence region. The promoter sequence region(s) may, independently, have a length such as, but not limited to, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600 and more than 600 nucleotides. The length of the promoter region for the viral genome may be 4-10, 10-20, 10-50, 20-30, 30-40, 40-50, 50-60, 50-100, 60-70, 70-80, 80-90, 90-100, 100-110, 100-150, 110-120, 120-130, 130-140, 140-150, 150-160, 150-200, 160-170, 170-180, 180-190, 190-200, 200-210, 200-250, 210-220, 220-230, 230-240, 240-250, 250-260, 250-300, 260-270, 270-280, 280-290, 290-300, 300-310, 300-350, 310-320, 320-330, 330-340, 340-350, 350-360, 350-400, 360-370, 370-380, 380-390, 390-400, 400-410, 400-450, 410-420, 420-430, 430-440, 440-450, 450-460, 450-500, 460-470, 470-480, 480-490, 490-500, 500-510, 500-550, 510-520, 520-530, 530-540, 540-550, 550-560, 550-600, 560-570, 570-580, 580-590, 590-600 and more than 600 nucleotides. As a non-limiting example, the viral genome comprises a promoter region that is about 260 nucleotides in length. As a non-limiting example, the viral genome comprises a promoter region that is about 283 nucleotides in length. As a non-limiting example, the viral genome comprises a promoter region that is about 299 nucleotides in length. As a non-limiting example, the viral genome comprises a promoter region that is about 365 nucleotides in length. As a non-limiting example, the viral genome comprises a promoter region that is about 380 nucleotides in length. As a non-limiting example, the viral genome comprises a promoter region that is about 382 nucleotides in length. As a non-limiting example, the viral genome comprises a promoter region that is about 557 nucleotides in length. As a non-limiting example, the viral genome comprises a promoter region that is about 654 nucleotides in length. As a non-limiting example, the viral genome comprises a promoter region that is about 699 nucleotides in length. As a non-limiting example, the viral genome comprises a promoter region that is about 1714 nucleotides in length. As a non-limiting example, the viral genome comprises a promoter region that is about 1715 nucleotides in length. As a non-limiting example, the viral genome comprises a promoter region that is about 1736 nucleotides in length.

In some embodiments, the AAV particle viral genome comprises at least one promoter sequence region. Non-limiting examples of promoter sequence regions are described in Table 8.

TABLE 8 Promoter Sequence Regions Sequence Sequence Region Name Length SEQ ID NO Promoter 1 1715 2080 Promoter 2 299 2081 Promoter 3 283 2082 Promoter 4 260 2083 Promoter 5 654 2084 Promoter 6 699 2085 Promoter 7 557 2086 Promoter 8 382 2087 Promoter 9 1736 2088 Promoter 10 365 2089 Promoter 11 1714 2238 Promoter 12 380 2239

In some embodiments, the AAV particle viral genome comprises one promoter sequence region. In some embodiments, the promoter sequence region is Promoter 1. In some embodiments, the promoter sequence region is Promoter 2. In some embodiments, the promoter sequence region is Promoter 3. In some embodiments, the promoter sequence region is Promoter 4. In some embodiments, the promoter sequence region is Promoter 5. In some embodiments, the promoter sequence region is Promoter 6. In some embodiments, the promoter sequence region is Promoter 7. In some embodiments, the promoter sequence region is Promoter 8. In some embodiments, the promoter sequence region is Promoter 9. In some embodiments, the promoter sequence region is Promoter 10. In some embodiments, the promoter sequence region is Promoter 11. In some embodiments, the promoter sequence region is Promoter 12. In some embodiments, the promoter sequence region further comprises at least one promoter sub-region. As a non-limiting example, the promoter sequence is Promoter 1, further comprising Promoter 2 and Promoter 3 sub-regions.

In some embodiments, the AAV particle viral genome comprises more than one promoter sequence region. In some embodiments, the AAV particle viral genome comprises two promoter sequence regions. In some embodiments, the AAV particle viral genome comprises three promoter sequence regions.

In some embodiments, the AAV particle viral genome may comprise at least one exon sequence region. The exon region(s) may, independently, have a length such as, but not limited to, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, and 150 nucleotides. The length of the exon region for the viral genome may be 2-10, 5-10, 5-15, 10-20, 10-30, 10-40, 15-20, 15-25, 20-30, 20-40, 20-50, 25-30, 25-35, 30-40, 30-50, 30-60, 35-40, 35-45, 40-50, 40-60, 40-70, 45-50, 45-55, 50-60, 50-70, 50-80, 55-60, 55-65, 60-70, 60-80, 60-90,65-70, 65-75, 70-80, 70-90, 70-100, 75-80, 75-85, 80-90, 80-100, 80-110, 85-90, 85-95, 90-100, 90-110, 90-120, 95-100, 95-105, 100-110, 100-120, 100-130, 105-110, 105-115, 110-120, 110-130, 110-140, 115-120, 115-125, 120-130, 120-140, 120-150, 125-130, 125-135, 130-140, 130-150, 135-140, 135-145, 140-150, and 145-150 nucleotides. As a non-limiting example, the viral genome comprises an exon region that is about 53 nucleotides in length. As a non-limiting example, the viral genome comprises an exon region that is about 54 nucleotides in length. As a non-limiting example, the viral genome comprises an exon region that is about 59 nucleotides in length. As a non-limiting example, the viral genome comprises an exon region that is about 102 nucleotides in length. As a non-limiting example, the viral genome comprises an exon region that is about 134 nucleotides in length.

In some embodiments, the AAV particle viral genome comprises at least one Exon sequence region. Non-limiting examples of Exon sequence regions are described in Table 9.

TABLE 9 Exon Sequence Regions Sequence Sequence Region Name Length SEQ ID NO Exon1 134 2090 Exon2 102 2091 Exon3 59 2092 Exon4 53 2093 Exon5 54 2094

In some embodiments, the AAV particle viral genome comprises one Exon sequence region. In some embodiments, the Exon sequence region is the Exon1 sequence region. In some embodiments, the Exon sequence region is the Exon2 sequence region. In some embodiments, the Exon sequence region is the Exon3 sequence region. In some embodiments, the Exon sequence region is the Exon4 sequence region. In some embodiments, the Exon sequence region is the Exon5 sequence region.

In some embodiments, the AAV particle viral genome comprises two Exon sequence regions. In some embodiments, the AAV particle viral genome comprises three Exon sequence regions. In some embodiments, the AAV particle viral genome comprises four Exon sequence regions. In some embodiments, the AAV particle viral genome comprises more than four Exon sequence regions.

In some embodiments, the AAV particle viral genome may comprise at least one intron sequence region. The intron region(s) may, independently, have a length such as, but not limited to, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350 and more than 350 nucleotides. The length of the intron region for the viral genome may be 25-35, 25-50, 35-45, 45-55, 50-75, 55-65, 65-75, 75-85, 75-100, 85-95, 95-105, 100-125, 105-115, 115-125, 125-135, 125-150, 135-145, 145-155, 150-175, 155-165, 165-175, 175-185, 175-200, 185-195, 195-205, 200-225, 205-215, 215-225, 225-235, 225-250, 235-245, 245-255, 250-275, 255-265, 265-275, 275-285, 275-300, 285-295, 295-305, 300-325, 305-315, 315-325, 325-335, 325-350, and 335-345 nucleotides. As a non-limiting example, the viral genome comprises an intron region that is about 15 nucleotides in length. As a non-limiting example, the viral genome comprises an intron region that is about 32 nucleotides in length. As a non-limiting example, the viral genome comprises an intron region that is about 41 nucleotides in length. As a non-limiting example, the viral genome comprises an intron region that is about 53 nucleotides in length. As a non-limiting example, the viral genome comprises an intron region that is about 73 nucleotides in length. As a non-limiting example, the viral genome comprises an intron region that is about 168 nucleotides in length. As a non-limiting example, the viral genome comprises an intron region that is about 172 nucleotides in length. As a non-limiting example, the viral genome comprises an intron region that is about 292 nucleotides in length. As a non-limiting example, the viral genome comprises an intron region that is about 347 nucleotides in length. As a non-limiting example, the viral genome comprises an intron region that is about 387 nucleotides in length. As a non-limiting example, the viral genome comprises an intron region that is about 491 nucleotides in length. As a non-limiting example, the viral genome comprises an intron region that is about 566 nucleotides in length. As a non-limiting example, the viral genome comprises an intron region that is about 1074 nucleotides in length.

In some embodiments, the AAV particle viral genome comprises at least one intron sequence region. Non-limiting examples of intron sequence regions are described in Table 10.

TABLE 10 Intron Sequence Regions Sequence Sequence Region Name Length SEQ ID NO Intron1 32 2095 Intron2 15 2096 Intron3 347 2097 Intron4 168 2098 Intron5 73 2099 Intron6 73 2100 Intron7 73 2101 Intron8 53 2102 Intron9 172 2103 Intron10 1074 2104 Intron11 41 2105 Intron12 566 2240 Intron13 491 2256 Intron14 387 2257 Intron15 292 2258

In some embodiments, the AAV particle viral genome comprises one intron sequence region. In some embodiments, the intron sequence region is the Intron 1 sequence region. In some embodiments, the intron sequence region is the Intron2 sequence region. In some embodiments, the intron sequence region is the Intron3 sequence region. In some embodiments, the intron sequence region is the Intron4 sequence region. In some embodiments, the intron sequence region is the Intron5 sequence region. In some embodiments, the intron sequence region is the Intron6 sequence region. In some embodiments, the intron sequence region is the Intron7 sequence region. In some embodiments, the intron sequence region is the Intron8 sequence region. In some embodiments, the intron sequence region is the Intron9 sequence region. In some embodiments, the intron sequence region is the Intron10 sequence region. In some embodiments, the intron sequence region is the Intron11 sequence region. In some embodiments, the intron sequence region is the Intron12 sequence region. In some embodiments, the intron sequence region is the Intron13 sequence region. In some embodiments, the intron sequence region is the Intron14 sequence region. In some embodiments, the intron sequence region is the Intron15 sequence region.

In some embodiments, the AAV particle viral genome comprises two intron sequence regions. In some embodiments, the AAV particle viral genome comprises three intron sequence regions. In some embodiments, the AAV particle viral genome comprises more than three intron sequence regions.

In some embodiments, the AAV particle viral genome may comprise at least one signal sequence region, not derived from an antibody. In another embodiment, the signal sequence region may be derived from an antibody sequence. The signal sequence region(s) may, independently, have a length such as, but not limited to, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, and 150 nucleotides. The length of the signal region in the viral genome may be 10-15, 15-25, 25-35, 25-50, 35-45, 45-55, 50-75, 55-65, 65-75, 75-85, 75-100, 85-95, 95-105, 100-125, 105-115, 115-125, 125-135, 125-150, 135-145, 145-155, 150-175, 155-165, 165-175, 175-185, 175-200, 185-195, 195-205, 200-225, 205-215, 215-225, 225-235, 225-250, 235-245, 245-255, 250-275, 255-265, 265-275, 275-285, 275-300, 285-295, 295-305, 300-325, 305-315, 315-325, 325-335, 325-350, and 335-345 nucleotides. As a non-limiting example, the viral genome comprises a signal sequence region that is about 12 nucleotides in length. As a non-limiting example, the viral genome comprises a signal sequence region that is about 57 nucleotides in length. As a non-limiting example, the viral genome comprises a signal sequence region that is about 66 nucleotides in length. As a non-limiting example, the viral genome comprises a signal sequence region that is about 69 nucleotides in length. As a non-limiting example, the viral genome comprises a signal sequence region that is about 72 nucleotides in length. As a non-limiting example, the viral genome comprises a signal sequence region that is about 78 nucleotides in length. As a non-limiting example, the viral genome comprises a signal sequence region that is about 81 nucleotides in length. As a non-limiting example, the viral genome comprises a signal sequence region that is about 84 nucleotides in length. As a non-limiting example, the viral genome comprises a signal sequence region that is about 93 nucleotides in length. As a non-limiting example, the viral genome comprises a signal sequence region that is about 96 nucleotides in length. As a non-limiting example, the viral genome comprises a signal sequence region that is about 411 nucleotides in length.

In some embodiments, the AAV particle viral genome comprises at least one signal sequence region. Non-limiting examples of signal sequence regions not derived from an antibody sequence are described in Table 11.

TABLE 11 Signal Sequence Regions Sequence Sequence Region Name Length SEQ ID NO Signal1 84 2106 Signal2 93 2107 Signal3 96 2108 Signal4 66 2109 Signal5 72 2110 Signal6 93 2111 Signal7 69 2112 Signal8 81 2113 Signal9 12 2114 Signal10 81 2115 Signal11 66 2116 Signal12 78 2117 Signal13 57 1740 Signal14 57 1741 Signal15 57 1861 Signal16 411 2241

In some embodiments, the AAV particle viral genome comprises one signal sequence region. In some embodiments, the signal sequence region is the Signal1 sequence region. In some embodiments, the signal sequence region is the Signal2 sequence region. In some embodiments, the signal sequence region is the Signal3 sequence region. In some embodiments, the signal sequence region is the Signal4 sequence region. In some embodiments, the signal sequence region is the Signal5 sequence region. In some embodiments, the signal sequence region is the Signal6 sequence region. In some embodiments, the signal sequence region is the Signal7 sequence region. In some embodiments, the signal sequence region is the Signal8 sequence region. In some embodiments, the signal sequence region is the Signal9 sequence region. In some embodiments, the signal sequence region is the Signal10 sequence region. In some embodiments, the signal sequence region is the Signal11 sequence region. In some embodiments, the signal sequence region is the Signal12 sequence region. In some embodiments, the signal sequence region is the Signal13 sequence region. In some embodiments, the signal sequence region is the Signal14 sequence region. In some embodiments, the signal sequence region is the Signal15 sequence region. In some embodiments, the signal sequence region is the Signal16 sequence region.

In some embodiments, the signal sequence is derived from an antibody sequence. As a non-limiting example, a signal sequence may be derived from the heavy chain or the light chain of an anti-tau antibody, such as, but not limited to, IPN002, PHF1 and/or MC1. While not wishing to be bound by theory, the first approximately 57 nucleotides of an antibody heavy chain or light chain sequence may be considered a signal sequence. Non-limiting examples of antibody derived signal sequences include Abi (SEQ ID NO: 1740), Ab2 (SEQ ID NO: 1741), and Ab122-124 (SEQ ID NO: 1861-1863), herein.

In some embodiments, the AAV particle viral genome comprises one signal sequence region. In some embodiments, the AAV particle viral genome comprises two signal sequence regions. In some embodiments, the AAV particle viral genome comprises three signal sequence regions. In some embodiments, the AAV particle viral genome comprises more than three signal sequence regions. In some embodiments, the signal sequences of a viral genome comprising more than one signal sequence, are the same. In another embodiment, the signal sequences of a viral genome comprising more than one signal sequence, are not the same.

In some embodiments, the AAV particle viral genome may comprise at least one tag sequence region. As used herein, the term “tag” indicates a polynucleotide sequence appended to the payload, that once expressed may be used to identify the expressed payload. Alternatively, the term “tag” may indicate a polynucleotide sequence appended to the payload that signals for retention of the expressed payload in a particular region of the cell (e.g., endoplasmic reticulum). The tag sequence region(s) may, independently, have a length such as, but not limited to, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more than 30 nucleotides. The length of the tag sequence region in the viral genome may be 10-15, 15-20, 20-25, 25-30, or more than 30 nucleotides. As a non-limiting example, the viral genome comprises a tag sequence region that is about 18 nucleotides in length. As a non-limiting example, the viral genome comprises a tag sequence region that is about 21 nucleotides in length. As a non-limiting example, the viral genome comprises a tag sequence region that is about 27 nucleotides in length.

In some embodiments, the AAV particle viral genome comprises at least one tag sequence region. Non-limiting examples of tag sequence regions are described in Table 12.

TABLE 12 Tag Sequence Regions Sequence Sequence Region Name Length SEQ ID NO Tag1 27 2118 Tag2 21 2119 Tag3 18 2120 Tag4 18 2121 Tag5 18 2255

In some embodiments, the AAV particle viral genome comprises one tag sequence region. In some embodiments, the tag sequence region is the Tag1 sequence region. In some embodiments, the tag sequence region is the Tag2 sequence region. In some embodiments, the tag sequence region is the Tag3 sequence region. In some embodiments, the tag sequence region is the Tag4 sequence region. In some embodiments, the tag sequence region is the Tag5 sequence region.

In some embodiments, the AAV particle viral genome comprises more than one tag sequence region. In some embodiments, the AAV particle viral genome comprises two tag sequence regions. In some embodiments, the AAV particle viral genome comprises three tag sequence regions. In some embodiments, the AAV particle viral genome comprises more than three tag sequence regions.

In some embodiments, the AAV particle viral genome may comprise at least one polyadenylation sequence region. The polyadenylation sequence region(s) may, independently, have a length such as, but not limited to, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, and 600 nucleotides. The length of the polyadenylation sequence region for the viral genome may be 4-10, 10-20, 10-50, 20-30, 30-40, 40-50, 50-60, 50-100, 60-70, 70-80, 80-90, 90-100, 100-110, 100-150, 110-120, 120-130, 130-140, 140-150, 150-160, 150-200, 160-170, 170-180, 180-190, 190-200, 200-210, 200-250, 210-220, 220-230, 230-240, 240-250, 250-260, 250-300, 260-270, 270-280, 280-290, 290-300, 300-310, 300-350, 310-320, 320-330, 330-340, 340-350, 350-360, 350-400, 360-370, 370-380, 380-390, 390-400, 400-410, 400-450, 410-420, 420-430, 430-440, 440-450, 450-460, 450-500, 460-470, 470-480, 480-490, 490-500, 500-510, 500-550, 510-520, 520-530, 530-540, 540-550, 550-560, 550-600, 560-570, 570-580, 580-590, and 590-600 nucleotides. As a non-limiting example, the viral genome comprises a polyadenylation sequence region that is about 127 nucleotides in length. As a non-limiting example, the viral genome comprises a polyadenylation sequence region that is about 477 nucleotides in length. As a non-limiting example, the viral genome comprises a polyadenylation sequence region that is about 552 nucleotides in length.

In some embodiments, the AAV particle viral genome comprises at least one polyadenylation (polyA) sequence region. Non-limiting examples of polyA sequence regions are described in Table 13.

TABLE 13 Poly-A Signal Sequence Regions Sequence Sequence Region Name Length SEQ ID NO PolyA1 127 2122 PolyA2 477 2123 PolyA3 552 2124

In some embodiments, the AAV particle viral genome comprises one polyA sequence region. In some embodiments, the polyA sequence region is the PolyA1 sequence. In some embodiments, the polyA sequence region is the PolyA2 sequence. In some embodiments, the polyA signal sequence region is the PolyA3 sequence.

In some embodiments, the AAV particle viral genome comprises more than one polyA sequence region.

In some embodiments, the AAV particle viral genome may comprise at least one or multiple filler sequence regions. The filler region(s) may, independently, have a length such as, but not limited to, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895, 896, 897, 898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031, 1032, 1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063, 1064, 1065, 1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079, 1080, 1081, 1082, 1083, 1084, 1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095, 1096, 1097, 1098, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107, 1108, 1109, 1110, 1111, 1112, 1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127, 1128, 1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144, 1145, 1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159, 1160, 1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175, 1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, 1218, 1219, 1220, 1221, 1222, 1223, 1224, 1225, 1226, 1227, 1228, 1229, 1230, 1231, 1232, 1233, 1234, 1235, 1236, 1237, 1238, 1239, 1240, 1241, 1242, 1243, 1244, 1245, 1246, 1247, 1248, 1249, 1250, 1251, 1252, 1253, 1254, 1255, 1256, 1257, 1258, 1259, 1260, 1261, 1262, 1263, 1264, 1265, 1266, 1267, 1268, 1269, 1270, 1271, 1272, 1273, 1274, 1275, 1276, 1277, 1278, 1279, 1280, 1281, 1282, 1283, 1284, 1285, 1286, 1287, 1288, 1289, 1290, 1291, 1292, 1293, 1294, 1295, 1296, 1297, 1298, 1299, 1300, 1301, 1302, 1303, 1304, 1305, 1306, 1307, 1308, 1309, 1310, 1311, 1312, 1313, 1314, 1315, 1316, 1317, 1318, 1319, 1320, 1321, 1322, 1323, 1324, 1325, 1326, 1327, 1328, 1329, 1330, 1331, 1332, 1333, 1334, 1335, 1336, 1337, 1338, 1339, 1340, 1341, 1342, 1343, 1344, 1345, 1346, 1347, 1348, 1349, 1350, 1351, 1352, 1353, 1354, 1355, 1356, 1357, 1358, 1359, 1360, 1361, 1362, 1363, 1364, 1365, 1366, 1367, 1368, 1369, 1370, 1371, 1372, 1373, 1374, 1375, 1376, 1377, 1378, 1379, 1380, 1381, 1382, 1383, 1384, 1385, 1386, 1387, 1388, 1389, 1390, 1391, 1392, 1393, 1394, 1395, 1396, 1397, 1398, 1399, 1400, 1401, 1402, 1403, 1404, 1405, 1406, 1407, 1408, 1409, 1410, 1411, 1412, 1413, 1414, 1415, 1416, 1417, 1418, 1419, 1420, 1421, 1422, 1423, 1424, 1425, 1426, 1427, 1428, 1429, 1430, 1431, 1432, 1433, 1434, 1435, 1436, 1437, 1438, 1439, 1440, 1441, 1442, 1443, 1444, 1445, 1446, 1447, 1448, 1449, 1450, 1451, 1452, 1453, 1454, 1455, 1456, 1457, 1458, 1459, 1460, 1461, 1462, 1463, 1464, 1465, 1466, 1467, 1468, 1469, 1470, 1471, 1472, 1473, 1474, 1475, 1476, 1477, 1478, 1479, 1480, 1481, 1482, 1483, 1484, 1485, 1486, 1487, 1488, 1489, 1490, 1491, 1492, 1493, 1494, 1495, 1496, 1497, 1498, 1499, 1500, 1501, 1502, 1503, 1504, 1505, 1506, 1507, 1508, 1509, 1510, 1511, 1512, 1513, 1514, 1515, 1516, 1517, 1518, 1519, 1520, 1521, 1522, 1523, 1524, 1525, 1526, 1527, 1528, 1529, 1530, 1531, 1532, 1533, 1534, 1535, 1536, 1537, 1538, 1539, 1540, 1541, 1542, 1543, 1544, 1545, 1546, 1547, 1548, 1549, 1550, 1551, 1552, 1553, 1554, 1555, 1556, 1557, 1558, 1559, 1560, 1561, 1562, 1563, 1564, 1565, 1566, 1567, 1568, 1569, 1570, 1571, 1572, 1573, 1574, 1575, 1576, 1577, 1578, 1579, 1580, 1581, 1582, 1583, 1584, 1585, 1586, 1587, 1588, 1589, 1590, 1591, 1592, 1593, 1594, 1595, 1596, 1597, 1598, 1599, 1600, 1601, 1602, 1603, 1604, 1605, 1606, 1607, 1608, 1609, 1610, 1611, 1612, 1613, 1614, 1615, 1616, 1617, 1618, 1619, 1620, 1621, 1622, 1623, 1624, 1625, 1626, 1627, 1628, 1629, 1630, 1631, 1632, 1633, 1634, 1635, 1636, 1637, 1638, 1639, 1640, 1641, 1642, 1643, 1644, 1645, 1646, 1647, 1648, 1649, 1650, 1651, 1652, 1653, 1654, 1655, 1656, 1657, 1658, 1659, 1660, 1661, 1662, 1663, 1664, 1665, 1666, 1667, 1668, 1669, 1670, 1671, 1672, 1673, 1674, 1675, 1676, 1677, 1678, 1679, 1680, 1681, 1682, 1683, 1684, 1685, 1686, 1687, 1688, 1689, 1690, 1691, 1692, 1693, 1694, 1695, 1696, 1697, 1698, 1699, 1700, 1701, 1702, 1703, 1704, 1705, 1706, 1707, 1708, 1709, 1710, 1711, 1712, 1713, 1714, 1715, 1716, 1717, 1718, 1719, 1720, 1721, 1722, 1723, 1724, 1725, 1726, 1727, 1728, 1729, 1730, 1731, 1732, 1733, 1734, 1735, 1736, 1737, 1738, 1739, 1740, 1741, 1742, 1743, 1744, 1745, 1746, 1747, 1748, 1749, 1750, 1751, 1752, 1753, 1754, 1755, 1756, 1757, 1758, 1759, 1760, 1761, 1762, 1763, 1764, 1765, 1766, 1767, 1768, 1769, 1770, 1771, 1772, 1773, 1774, 1775, 1776, 1777, 1778, 1779, 1780, 1781, 1782, 1783, 1784, 1785, 1786, 1787, 1788, 1789, 1790, 1791, 1792, 1793, 1794, 1795, 1796, 1797, 1798, 1799, 1800, 1801, 1802, 1803, 1804, 1805, 1806, 1807, 1808, 1809, 1810, 1811, 1812, 1813, 1814, 1815, 1816, 1817, 1818, 1819, 1820, 1821, 1822, 1823, 1824, 1825, 1826, 1827, 1828, 1829, 1830, 1831, 1832, 1833, 1834, 1835, 1836, 1837, 1838, 1839, 1840, 1841, 1842, 1843, 1844, 1845, 1846, 1847, 1848, 1849, 1850, 1851, 1852, 1853, 1854, 1855, 1856, 1857, 1858, 1859, 1860, 1861, 1862, 1863, 1864, 1865, 1866, 1867, 1868, 1869, 1870, 1871, 1872, 1873, 1874, 1875, 1876, 1877, 1878, 1879, 1880, 1881, 1882, 1883, 1884, 1885, 1886, 1887, 1888, 1889, 1890, 1891, 1892, 1893, 1894, 1895, 1896, 1897, 1898, 1899, 1900, 1901, 1902, 1903, 1904, 1905, 1906, 1907, 1908, 1909, 1910, 1911, 1912, 1913, 1914, 1915, 1916, 1917, 1918, 1919, 1920, 1921, 1922, 1923, 1924, 1925, 1926, 1927, 1928, 1929, 1930, 1931, 1932, 1933, 1934, 1935, 1936, 1937, 1938, 1939, 1940, 1941, 1942, 1943, 1944, 1945, 1946, 1947, 1948, 1949, 1950, 1951, 1952, 1953, 1954, 1955, 1956, 1957, 1958, 1959, 1960, 1961, 1962, 1963, 1964, 1965, 1966, 1967, 1968, 1969, 1970, 1971, 1972, 1973, 1974, 1975, 1976, 1977, 1978, 1979, 1980, 1981, 1982, 1983, 1984, 1985, 1986, 1987, 1988, 1989, 1990, 1991, 1992, 1993, 1994, 1995, 1996, 1997, 1998, 1999, 2000, 2001, 2002, 2003, 2004, 2005, 2006, 2007, 2008, 2009, 2010, 2011, 2012, 2013, 2014, 2015, 2016, 2017, 2018, 2019, 2020, 2021, 2022, 2023, 2024, 2025, 2026, 2027, 2028, 2029, 2030, 2031, 2032, 2033, 2034, 2035, 2036, 2037, 2038, 2039, 2040, 2041, 2042, 2043, 2044, 2045, 2046, 2047, 2048, 2049, 2050, 2051, 2052, 2053, 2054, 2055, 2056, 2057, 2058, 2059, 2060, 2061, 2062, 2063, 2064, 2065, 2066, 2067, 2068, 2069, 2070, 2071, 2072, 2073, 2074, 2075, 2076, 2077, 2078, 2079, 2080, 2081, 2082, 2083, 2084, 2085, 2086, 2087, 2088, 2089, 2090, 2091, 2092, 2093, 2094, 2095, 2096, 2097, 2098, 2099, 2100, 2101, 2102, 2103, 2104, 2105, 2106, 2107, 2108, 2109, 2110, 2111, 2112, 2113, 2114, 2115, 2116, 2117, 2118, 2119, 2120, 2121, 2122, 2123, 2124, 2125, 2126, 2127, 2128, 2129, 2130, 2131, 2132, 2133, 2134, 2135, 2136, 2137, 2138, 2139, 2140, 2141, 2142, 2143, 2144, 2145, 2146, 2147, 2148, 2149, 2150, 2151, 2152, 2153, 2154, 2155, 2156, 2157, 2158, 2159, 2160, 2161, 2162, 2163, 2164, 2165, 2166, 2167, 2168, 2169, 2170, 2171, 2172, 2173, 2174, 2175, 2176, 2177, 2178, 2179, 2180, 2181, 2182, 2183, 2184, 2185, 2186, 2187, 2188, 2189, 2190, 2191, 2192, 2193, 2194, 2195, 2196, 2197, 2198, 2199, 2200, 2201, 2202, 2203, 2204, 2205, 2206, 2207, 2208, 2209, 2210, 2211, 2212, 2213, 2214, 2215, 2216, 2217, 2218, 2219, 2220, 2221, 2222, 2223, 2224, 2225, 2226, 2227, 2228, 2229, 2230, 2231, 2232, 2233, 2234, 2235, 2236, 2237, 2238, 2239, 2240, 2241, 2242, 2243, 2244, 2245, 2246, 2247, 2248, 2249, 2250, 2251, 2252, 2253, 2254, 2255, 2256, 2257, 2258, 2259, 2260, 2261, 2262, 2263, 2264, 2265, 2266, 2267, 2268, 2269, 2270, 2271, 2272, 2273, 2274, 2275, 2276, 2277, 2278, 2279, 2280, 2281, 2282, 2283, 2284, 2285, 2286, 2287, 2288, 2289, 2290, 2291, 2292, 2293, 2294, 2295, 2296, 2297, 2298, 2299, 2300, 2301, 2302, 2303, 2304, 2305, 2306, 2307, 2308, 2309, 2310, 2311, 2312, 2313, 2314, 2315, 2316, 2317, 2318, 2319, 2320, 2321, 2322, 2323, 2324, 2325, 2326, 2327, 2328, 2329, 2330, 2331, 2332, 2333, 2334, 2335, 2336, 2337, 2338, 2339, 2340, 2341, 2342, 2343, 2344, 2345, 2346, 2347, 2348, 2349, 2350, 2351, 2352, 2353, 2354, 2355, 2356, 2357, 2358, 2359, 2360, 2361, 2362, 2363, 2364, 2365, 2366, 2367, 2368, 2369, 2370, 2371, 2372, 2373, 2374, 2375, 2376, 2377, 2378, 2379, 2380, 2381, 2382, 2383, 2384, 2385, 2386, 2387, 2388, 2389, 2390, 2391, 2392, 2393, 2394, 2395, 2396, 2397, 2398, 2399, 2400, 2401, 2402, 2403, 2404, 2405, 2406, 2407, 2408, 2409, 2410, 2411, 2412, 2413, 2414, 2415, 2416, 2417, 2418, 2419, 2420, 2421, 2422, 2423, 2424, 2425, 2426, 2427, 2428, 2429, 2430, 2431, 2432, 2433, 2434, 2435, 2436, 2437, 2438, 2439, 2440, 2441, 2442, 2443, 2444, 2445, 2446, 2447, 2448, 2449, 2450, 2451, 2452, 2453, 2454, 2455, 2456, 2457, 2458, 2459, 2460, 2461, 2462, 2463, 2464, 2465, 2466, 2467, 2468, 2469, 2470, 2471, 2472, 2473, 2474, 2475, 2476, 2477, 2478, 2479, 2480, 2481, 2482, 2483, 2484, 2485, 2486, 2487, 2488, 2489, 2490, 2491, 2492, 2493, 2494, 2495, 2496, 2497, 2498, 2499, 2500, 2501, 2502, 2503, 2504, 2505, 2506, 2507, 2508, 2509, 2510, 2511, 2512, 2513, 2514, 2515, 2516, 2517, 2518, 2519, 2520, 2521, 2522, 2523, 2524, 2525, 2526, 2527, 2528, 2529, 2530, 2531, 2532, 2533, 2534, 2535, 2536, 2537, 2538, 2539, 2540, 2541, 2542, 2543, 2544, 2545, 2546, 2547, 2548, 2549, 2550, 2551, 2552, 2553, 2554, 2555, 2556, 2557, 2558, 2559, 2560, 2561, 2562, 2563, 2564, 2565, 2566, 2567, 2568, 2569, 2570, 2571, 2572, 2573, 2574, 2575, 2576, 2577, 2578, 2579, 2580, 2581, 2582, 2583, 2584, 2585, 2586, 2587, 2588, 2589, 2590, 2591, 2592, 2593, 2594, 2595, 2596, 2597, 2598, 2599, 2600, 2601, 2602, 2603, 2604, 2605, 2606, 2607, 2608, 2609, 2610, 2611, 2612, 2613, 2614, 2615, 2616, 2617, 2618, 2619, 2620, 2621, 2622, 2623, 2624, 2625, 2626, 2627, 2628, 2629, 2630, 2631, 2632, 2633, 2634, 2635, 2636, 2637, 2638, 2639, 2640, 2641, 2642, 2643, 2644, 2645, 2646, 2647, 2648, 2649, 2650, 2651, 2652, 2653, 2654, 2655, 2656, 2657, 2658, 2659, 2660, 2661, 2662, 2663, 2664, 2665, 2666, 2667, 2668, 2669, 2670, 2671, 2672, 2673, 2674, 2675, 2676, 2677, 2678, 2679, 2680, 2681, 2682, 2683, 2684, 2685, 2686, 2687, 2688, 2689, 2690, 2691, 2692, 2693, 2694, 2695, 2696, 2697, 2698, 2699, 2700, 2701, 2702, 2703, 2704, 2705, 2706, 2707, 2708, 2709, 2710, 2711, 2712, 2713, 2714, 2715, 2716, 2717, 2718, 2719, 2720, 2721, 2722, 2723, 2724, 2725, 2726, 2727, 2728, 2729, 2730, 2731, 2732, 2733, 2734, 2735, 2736, 2737, 2738, 2739, 2740, 2741, 2742, 2743, 2744, 2745, 2746, 2747, 2748, 2749, 2750, 2751, 2752, 2753, 2754, 2755, 2756, 2757, 2758, 2759, 2760, 2761, 2762, 2763, 2764, 2765, 2766, 2767, 2768, 2769, 2770, 2771, 2772, 2773, 2774, 2775, 2776, 2777, 2778, 2779, 2780, 2781, 2782, 2783, 2784, 2785, 2786, 2787, 2788, 2789, 2790, 2791, 2792, 2793, 2794, 2795, 2796, 2797, 2798, 2799, 2800, 2801, 2802, 2803, 2804, 2805, 2806, 2807, 2808, 2809, 2810, 2811, 2812, 2813, 2814, 2815, 2816, 2817, 2818, 2819, 2820, 2821, 2822, 2823, 2824, 2825, 2826, 2827, 2828, 2829, 2830, 2831, 2832, 2833, 2834, 2835, 2836, 2837, 2838, 2839, 2840, 2841, 2842, 2843, 2844, 2845, 2846, 2847, 2848, 2849, 2850, 2851, 2852, 2853, 2854, 2855, 2856, 2857, 2858, 2859, 2860, 2861, 2862, 2863, 2864, 2865, 2866, 2867, 2868, 2869, 2870, 2871, 2872, 2873, 2874, 2875, 2876, 2877, 2878, 2879, 2880, 2881, 2882, 2883, 2884, 2885, 2886, 2887, 2888, 2889, 2890, 2891, 2892, 2893, 2894, 2895, 2896, 2897, 2898, 2899, 2900, 2901, 2902, 2903, 2904, 2905, 2906, 2907, 2908, 2909, 2910, 2911, 2912, 2913, 2914, 2915, 2916, 2917, 2918, 2919, 2920, 2921, 2922, 2923, 2924, 2925, 2926, 2927, 2928, 2929, 2930, 2931, 2932, 2933, 2934, 2935, 2936, 2937, 2938, 2939, 2940, 2941, 2942, 2943, 2944, 2945, 2946, 2947, 2948, 2949, 2950, 2951, 2952, 2953, 2954, 2955, 2956, 2957, 2958, 2959, 2960, 2961, 2962, 2963, 2964, 2965, 2966, 2967, 2968, 2969, 2970, 2971, 2972, 2973, 2974, 2975, 2976, 2977, 2978, 2979, 2980, 2981, 2982, 2983, 2984, 2985, 2986, 2987, 2988, 2989, 2990, 2991, 2992, 2993, 2994, 2995, 2996, 2997, 2998, 2999, 3000, 3001, 3002, 3003, 3004, 3005, 3006, 3007, 3008, 3009, 3010, 3011, 3012, 3013, 3014, 3015, 3016, 3017, 3018, 3019, 3020, 3021, 3022, 3023, 3024, 3025, 3026, 3027, 3028, 3029, 3030, 3031, 3032, 3033, 3034, 3035, 3036, 3037, 3038, 3039, 3040, 3041, 3042, 3043, 3044, 3045, 3046, 3047, 3048, 3049, 3050, 3051, 3052, 3053, 3054, 3055, 3056, 3057, 3058, 3059, 3060, 3061, 3062, 3063, 3064, 3065, 3066, 3067, 3068, 3069, 3070, 3071, 3072, 3073, 3074, 3075, 3076, 3077, 3078, 3079, 3080, 3081, 3082, 3083, 3084, 3085, 3086, 3087, 3088, 3089, 3090, 3091, 3092, 3093, 3094, 3095, 3096, 3097, 3098, 3099, 3100, 3101, 3102, 3103, 3104, 3105, 3106, 3107, 3108, 3109, 3110, 3111, 3112, 3113, 3114, 3115, 3116, 3117, 3118, 3119, 3120, 3121, 3122, 3123, 3124, 3125, 3126, 3127, 3128, 3129, 3130, 3131, 3132, 3133, 3134, 3135, 3136, 3137, 3138, 3139, 3140, 3141, 3142, 3143, 3144, 3145, 3146, 3147, 3148, 3149, 3150, 3151, 3152, 3153, 3154, 3155, 3156, 3157, 3158, 3159, 3160, 3161, 3162, 3163, 3164, 3165, 3166, 3167, 3168, 3169, 3170, 3171, 3172, 3173, 3174, 3175, 3176, 3177, 3178, 3179, 3180, 3181, 3182, 3183, 3184, 3185, 3186, 3187, 3188, 3189, 3190, 3191, 3192, 3193, 3194, 3195, 3196, 3197, 3198, 3199, 3200, 3201, 3202, 3203, 3204, 3205, 3206, 3207, 3208, 3209, 3210, 3211, 3212, 3213, 3214, 3215, 3216, 3217, 3218, 3219, 3220, 3221, 3222, 3223, 3224, 3225, 3226, 3227, 3228, 3229, 3230, 3231, 3232, 3233, 3234, 3235, 3236, 3237, 3238, 3239, 3240, 3241, 3242, 3243, 3244, 3245, 3246, 3247, 3248, 3249, and 3250 nucleotides. The length of any filler region for the viral genome may be 50-100, 100-150, 150-200, 200-250, 250-300, 300-350, 350-400, 400-450, 450-500, 500-550, 550-600, 600-650, 650-700, 700-750, 750-800, 800-850, 850-900,900-950, 950-1000, 1000-1050, 1050-1100, 1100-1150, 1150-1200, 1200-1250, 1250-1300, 1300-1350, 1350-1400, 1400-1450, 1450-1500, 1500-1550, 1550-1600, 1600-1650, 1650-1700, 1700-1750, 1750-1800, 1800-1850, 1850-1900, 1900-1950, 1950-2000, 2000-2050, 2050-2100, 2100-2150, 2150-2200, 2200-2250, 2250-2300, 2300-2350, 2350-2400, 2400-2450, 2450-2500, 2500-2550, 2550-2600, 2600-2650, 2650-2700, 2700-2750, 2750-2800, 2800-2850, 2850-2900, 2900-2950, 2950-3000, 3000-3050, 3050-3100, 3100-3150, 3150-3200, and 3200-3250 nucleotides. As a non-limiting example, the viral genome comprises a filler region that is about 1153 nucleotides in length. As a non-limiting example, the viral genome comprises a filler region that is about 1240 nucleotides in length.

In some embodiments, the AAV particle viral genome comprises at least one filler sequence region. Non-limiting examples of filler sequence regions are described in Table 14.

TABLE 14 Filler Sequence Regions Sequence Sequence Region Name Length SEQ ID NO FILLER1 1153 2125 FILLER2 1240 2126

In some embodiments, the AAV particle viral genome comprises filler sequence region FILLER1. In some embodiments, the AAV particle viral genome comprises filler sequence region FILLER2. In some embodiments, the AAV particle viral genome comprises both FILLER1 and FILLER2. In some embodiments, the AAV particle viral genome does not comprise a filler sequence region.

In some embodiments, the AAV particle viral genome may comprise any of the sequences shown in Tables 15-91.

TABLE 15 Sequence Regions in ITR to ITR Sequences TAU_ITR1 TAU_ITR2 (SEQ ID NO: 1990) (SEQ ID NO: 1991) Sequence Region Region Region Region Regions SEQ ID NO length SEQ ID NO length 5′ ITR 2076 130 2076 130 CAG 2080 1715 2080 1715 promoter CMVie 2081 299 2081 299 CBA min. 2082 283 2082 283 Signal 1740 57 1740 57 VH 1821 351 1821 351 Constant 1742 969 1742 969 Linker 1724 12 1725 12 Linker 1726 54 1727 75 Signal 1861 57 1861 57 VL 1939 336 1939 336 Constant 1864 321 1864 321 PolyA 2122 127 2122 127 3′ ITR 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 1990 (TAU_ITR1) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, an IPN002 antibody heavy chain signal sequence, an IPN002 antibody heavy chain variable region and heavy chain constant region, a furin cleavage site, a T2A linker, an IPN002 antibody light chain signal sequence, an IPN002 antibody light chain variable region and light chain constant region, and a rabbit globin polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 3815 (TAU_ITR2) which comprises a 5 inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, an IPN002 antibody heavy chain signal sequence, an IPN002 antibody heavy chain variable region and heavy chain constant region, a furin cleavage site, an F2A linker, an IPN002 antibody light chain signal sequence, an IPN002 antibody light chain variable region and light chain constant region, and a rabbit globin polyadenylation sequence.

TABLE 16 Sequence Regions in ITR to ITR Sequences TAU_ITR3 TAU_ITR4 (SEQ ID NO: 1992) (SEQ ID NO: 1993) Sequence Region Region Region Region Regions SEQ ID NO length SEQ ID NO length 5′ ITR 2076 130 2076 130 CB 2083 260 2083 260 promoter Exon 2090 134 2090 134 Intron 2095 32 2095 32 Intron 2097 347 2097 347 Exon 2093 53 2093 53 Signal 1740 57 1740 57 VH 1821 351 1821 351 Constant 1742 969 1742 969 Linker 1725 12 1724 12 Linker 1727 75 1726 54 Signal 1861 57 1861 57 VL 1939 336 1939 336 Constant 1864 321 1864 321 PolyA 2122 127 2122 127 3′ ITR 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 1992 (TAU_ITR3) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CB promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody heavy chain signal sequence, an IPN002 antibody heavy chain variable region and heavy chain constant region, a furin cleavage site, an F2A linker, an IPN002 antibody light chain signal sequence, an IPN002 antibody light chain variable region and light chain constant region, and a rabbit globin polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 1993 (TAU_ITR4) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CB promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody heavy chain signal sequence, an IPN002 antibody heavy chain variable region and heavy chain constant region, a furin cleavage site, a T2A linker, an IPN002 antibody light chain signal sequence, an IPN002 antibody light chain variable region and light chain constant region, and a rabbit globin polyadenylation sequence.

TABLE 17 Sequence Regions in ITR to ITR Sequences TAU_ITR5 TAU_ITR6 TAU_ITR7 TAU_ITR8 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 1994) 1995) 1996) 1997) Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 Promoter 2085 699 2085 699 2086 557 2086 557 Exon 2090 134 2090 134 2090 134 2090 134 Intron 2095 32 2095 32 2095 32 2095 32 Intron 2097 347 2097 347 2097 347 2097 347 Exon 2093 53 2093 53 2093 53 2093 53 Signal 1740 57 1740 57 1740 57 1740 57 VH 1821 351 1821 351 1821 351 1821 351 Constant 1742 969 1742 969 1742 969 1742 969 Linker 1725 12 1724 12 1725 12 1724 12 Linker 1727 75 1726 54 1727 75 1726 54 Signal 1861 57 1861 57 1861 57 1861 57 VL 1939 336 1939 336 1939 336 1939 336 Constant 1864 321 1864 321 1864 321 1864 321 Poly A 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 1994 (TAU_ITR5) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody heavy chain signal sequence, an IPN002 antibody heavy chain variable region and heavy chain constant region, a furin cleavage site, an F2A linker, an IPN002 antibody light chain signal sequence, an IPN002 antibody light chain variable region and light chain constant region, and a rabbit globin polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 1995 (TAU_ITR6) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody heavy chain signal sequence, an IPN002 antibody heavy chain variable region and heavy chain constant region, a furin cleavage site, a T2A linker, an IPN002 antibody light chain signal sequence, an IPN002 antibody light chain variable region and light chain constant region, and a rabbit globin polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 1996 (TAU_ITR7) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a synapsin promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody heavy chain signal sequence, an IPN002 antibody heavy chain variable region and heavy chain constant region, a furin cleavage site, an F2A linker, an IPN002 antibody light chain signal sequence, an IPN002 antibody light chain variable region and light chain constant region, and a rabbit globin polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 1997 (TAU_ITR8) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a synapsin promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody heavy chain signal sequence, an IPN002 antibody heavy chain variable region and heavy chain constant region, a furin cleavage site, a T2A linker, an IPN002 antibody light chain signal sequence, an IPN002 antibody light chain variable region and light chain constant region, and a rabbit globin polyadenylation sequence.

TABLE 18 Sequence Regions in ITR to ITR Sequences TAU_ITR9 TAU_ITR10 (SEQ ID NO: 1998) (SEQ ID NO: 1999) Sequence Region Region Region Region Regions SEQ ID NO length SEQ ID NO length 5′ ITR 2076 130 2076 130 CAG promoter 2080 1715 2080 1715 CMVie 2081 299 2081 299 CBA min. 2082 283 2082 283 Signal 1861 57 1861 57 VL 1939 336 1939 336 Constant 1864 321 1864 321 Linker 1727 75 1726 54 Signal 1740 57 1740 57 VH 1821 351 1821 351 Constant 1742 969 1742 969 PolyA 2122 127 2122 127 3′ ITR 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 1998 (TAU_ITR9) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, an IPN002 antibody light chain signal sequence, an IPN002 antibody light chain variable region and light chain constant region, an F2A linker, an IPN002 antibody heavy chain signal sequence, an IPN002 antibody heavy chain variable region and heavy chain constant region, and a rabbit globin polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 1999 (TAU_ITR10) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, an IPN002 antibody light chain signal sequence, an IPN002 antibody light chain variable region and light chain constant region, a T2A linker, an IPN002 antibody heavy chain signal sequence, an IPN002 antibody heavy chain variable region and heavy chain constant region, and a rabbit globin polyadenylation sequence.

TABLE 19 Sequence Regions in ITR to ITR Sequences TAU_ITR11 TAU_ITR87 (SEQ ID NO: 2000) (SEQ ID NO: 2137) Sequence Region Region Region Region Regions SEQ ID NO length SEQ ID NO length 5′ ITR 2076 130 2076 130 Promoter 2083 260 2083 260 Exon 2090 134 2090 134 Intron 2095 32 2095 32 Intron 2097 347 2097 347 Exon 2093 53 2093 53 Signal 1861 57 1861 57 VL 1939 336 1939 336 Constant 1864 321 1864 321 Linker 1727 75 1726 54 Signal 1740 57 1740 57 VH 1821 351 1821 351 Constant 1742 969 1742 969 PolyA 2122 127 2122 127 3′ ITR 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2000 (TAU_ITR11) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CB promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody light chain signal sequence, an IPN002 antibody light chain variable region and light chain constant region, an F2A linker, an IPN002 antibody heavy chain signal sequence, an IPN002 antibody heavy chain variable region and heavy chain constant region, and a rabbit globin polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2137 (TAU_ITR87) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CB promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody light chain signal sequence, an IPN002 antibody light chain variable region and light chain constant region, an T2A linker, an IPN002 antibody heavy chain signal sequence, an IPN002 antibody heavy chain variable region and heavy chain constant region, and a rabbit globin polyadenylation sequence.

TABLE 20 Sequence Regions in ITR to ITR Sequences TAU_ITR12 TAU_ITR13 TAU_ITR14 TAU_ITR15 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2001) 2002) 2003) 2004) Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 Promoter 2085 699 2085 699 2086 557 2086 557 Exon 2090 134 2090 134 2090 134 2090 134 Intron 2095 32 2095 32 2095 32 2095 32 Intron 2097 347 2097 347 2097 347 2097 347 Exon 2093 53 2093 53 2093 53 2093 53 Signal 1861 57 1861 57 1861 57 1861 57 VL 1939 336 1939 336 1939 336 1939 336 Constant 1864 321 1864 321 1864 321 1864 321 Linker 1727 75 1726 54 1727 75 1726 54 Signal 1740 57 1740 57 1740 57 1740 57 VH 1821 351 1821 351 1821 351 1821 351 Constant 1742 969 1742 969 1742 969 1742 969 Poly A 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2001 (TAU_ITR12) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody light chain signal sequence, an IPN002 antibody light chain variable region and light chain constant region, an F2A linker, an IPN002 antibody heavy chain signal sequence, an IPN002 antibody heavy chain variable region and heavy chain constant region, and a rabbit globin polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2002 (TAU_ITR13) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody light chain signal sequence, an IPN002 antibody light chain variable region and light chain constant region, a T2A linker, an IPN002 antibody heavy chain signal sequence, an IPN002 antibody heavy chain variable region and heavy chain constant region, and a rabbit globin polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2003 (TAU_ITR14) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a synapsin promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody light chain signal sequence, an IPN002 antibody light chain variable region and light chain constant region, an F2A linker, an IPN002 antibody heavy chain signal sequence, an IPN002 antibody heavy chain variable region and heavy chain constant region, and a rabbit globin polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2004 (TAU_ITR15) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a synapsin promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody light chain signal sequence, an IPN002 antibody light chain variable region and light chain constant region, a T2A linker, an IPN002 antibody heavy chain signal sequence, an IPN002 antibody heavy chain variable region and heavy chain constant region, and a rabbit globin polyadenylation sequence.

TABLE 21 Sequence Regions in ITR to ITR Sequences TAU_ITR16 TAU_ITR17 TAU_ITR18 TAU_ITR19 TAU_ITR20 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2005) 2006) 2007) 2008) 2009) Region Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 2076 130 Promoter 2083 260 2083 260 2083 260 2083 260 2083 260 Exon 2090 134 2090 134 2090 134 2090 134 2090 134 Intron 2095 32 2095 32 2095 32 2095 32 2095 32 Intron 2097 347 2097 347 2097 347 2097 347 2097 347 Exon 2093 53 2093 53 2093 53 2093 53 2093 53 Signal 1861 57 1861 57 1861 57 1861 57 1861 57 VL 1921 321 1922 321 1923 321 1924 321 1925 321 Constant 1864 321 1864 321 1864 321 1864 321 1864 321 Linker 1726 54 1726 54 1726 54 1726 54 1726 54 Signal 1740 57 1740 57 1740 57 1740 57 1740 57 VH 1804 345 1805 345 1806 345 1807 345 1808 345 Constant 1743 972 1743 972 1743 972 1743 972 1743 972 Poly A 2122 127 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2005 (TAU_ITR16) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CB promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody light chain signal sequence, a codon-optimized (Bioinformatics) C10.2 antibody light chain variable region, a light chain constant region, a T2A linker, an IPN002 antibody heavy chain signal sequence, a codon-optimized C10.2 antibody heavy chain variable region, a heavy chain constant region, and a rabbit globin polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2006 (TAU_ITR17) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CB promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody light chain signal sequence, a codon-optimized (EMBOSS) C10.2 antibody light chain variable region, a light chain constant region, a T2A linker, an IPN002 antibody heavy chain signal sequence, a codon-optimized C10.2 antibody heavy chain variable region, a heavy chain constant region, and a rabbit globin polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2007 (TAU_ITR18) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CB promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody light chain signal sequence, a codon-optimized (GeneInfinity) C10.2 antibody light chain variable region, a light chain constant region, a T2A linker, an IPN002 antibody heavy chain signal sequence, a codon-optimized C10.2 antibody heavy chain variable region, a heavy chain constant region, and a rabbit globin polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2008 (TAU_ITR19) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CB promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody light chain signal sequence, a codon-optimized (GregThatcher) C10.2 antibody light chain variable region, a light chain constant region, a T2A linker, an IPN002 antibody heavy chain signal sequence, a codon-optimized C10.2 antibody heavy chain variable region, a heavy chain constant region, and a rabbit globin polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2009 (TAU_ITR20) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CB promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody light chain signal sequence, a codon-optimized (IDT) C10.2 antibody light chain variable region, a light chain constant region, a T2A linker, an IPN002 antibody heavy chain signal sequence, a codon-optimized C10.2 antibody heavy chain variable region, a heavy chain constant region, and a rabbit globin polyadenylation sequence.

TABLE 22 Sequence Regions in ITR to ITR Sequences TAU_ITR21 TAU_ITR22 TAU_ITR23 TAU_ITR24 TAU_ITR25 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2010) 2011) 2012) 2013) 2014) Region Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 2076 130 Promoter 2083 260 2083 260 2083 260 2083 260 2083 260 Exon 2090 134 2090 134 2090 134 2090 134 2090 134 Intron 2095 32 2095 32 2095 32 2095 32 2095 32 Intron 2097 347 2097 347 2097 347 2097 347 2097 347 Exon 2093 53 2093 53 2093 53 2093 53 2093 53 Signal 1861 57 1861 57 1861 57 1861 57 1861 57 VL 1926 321 1927 321 1928 321 1929 321 1930 321 Constant 1864 321 1864 321 1864 321 1864 321 1864 321 Linker 1726 54 1726 54 1726 54 1726 54 1726 54 Signal 1740 57 1740 57 1740 57 1740 57 1740 57 VH 1809 345 1810 345 1811 345 1812 345 1813 345 Constant 1743 972 1743 972 1743 972 1743 972 1743 972 Poly A 2122 127 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2010 (TAU_ITR21) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CB promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody light chain signal sequence, a codon-optimized (InSilico) C10.2 antibody light chain variable region, a light chain constant region, a T2A linker, an IPN002 antibody heavy chain signal sequence, a codon-optimized C10.2 antibody heavy chain variable region, a heavy chain constant region, and a rabbit globin polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2011 (TAU_ITR22) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CB promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody light chain signal sequence, a codon-optimized (MolBio) C10.2 antibody light chain variable region, a light chain constant region, a T2A linker, an IPN002 antibody heavy chain signal sequence, a codon-optimized C10.2 antibody heavy chain variable region, a heavy chain constant region, and a rabbit globin polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2012 (TAU_ITR23) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CB promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody light chain signal sequence, a codon-optimized (N2P) C10.2 antibody light chain variable region, a light chain constant region, a T2A linker, an IPN002 antibody heavy chain signal sequence, a codon-optimized C10.2 antibody heavy chain variable region, a heavy chain constant region, and a rabbit globin polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2013 (TAU_ITR24) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CB promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody light chain signal sequence, a codon-optimized (SnapGene) C10.2 antibody light chain variable region, a light chain constant region, a T2A linker, an IPN002 antibody heavy chain signal sequence, a codon-optimized C10.2 antibody heavy chain variable region, a heavy chain constant region, and a rabbit globin polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2014 (TAU_ITR25) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CB promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody light chain signal sequence, a codon-optimized (Vector NTI) C10.2 antibody light chain variable region, a light chain constant region, a T2A linker, an IPN002 antibody heavy chain signal sequence, a codon-optimized C10.2 antibody heavy chain variable region, a heavy chain constant region, and a rabbit globin polyadenylation sequence.

TABLE 23 Sequence Regions in ITR to ITR Sequences TAU_ITR26 TAU_ITR27 TAU_ITR28 TAU_ITR29 TAU_ITR30 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2015) 2016) 2017) 2018) 2019) Region Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length ID NO length 5′ ITR 2077 141 2077 141 2077 141 2077 141 2077 141 Promoter 2084 654 2084 654 2084 654 2084 654 2084 654 Exon 2090 134 2090 134 2090 134 2090 134 2090 134 Intron 2095 32 2095 32 2095 32 2095 32 2095 32 Intron 2097 347 2097 347 2097 347 2097 347 2097 347 Exon 2093 53 2093 53 2093 53 2093 53 2093 53 Signal 1740 57 — — 1740 57 1740 57 1740 57 VH 1854 354 1859 354 1852 354 1850 354 1856 354 Constant 1742 969 1742 969 1742 969 1742 969 1742 969 Linker 1724 12 1724 12 1724 12 1724 12 1724 12 Linker 1726 54 1726 54 1726 54 1726 54 1726 54 Signal 1861 57 1861 57 1861 57 1861 57 1861 57 VL 1975 321 1980 321 1973 321 1971 321 1977 321 Constant 1864 321 1864 321 1864 321 1864 321 1864 321 Poly A 2123 477 2123 477 2123 477 2123 477 2123 477 3′ HR 2079 141 2079 141 2079 141 2079 141 2079 141

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2015 (TAU_ITR26) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody heavy chain signal sequence, a codon-optimized (GeneScript) PT3 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, an IPN002 antibody light chain signal sequence, a codon-optimized PT3 antibody light chain variable region, a light chain constant region, and a human growth hormone polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2016 (TAU_ITR27) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, a codon-optimized (SnapGene) PT3 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, an IPN002 antibody light chain signal sequence, a codon-optimized PT3 antibody light chain variable region, a light chain constant region, and a human growth hormone polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2017 (TAU_ITR28) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody heavy chain signal sequence, a codon-optimized (EMBOSS) PT3 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, an IPN002 antibody light chain signal sequence, a codon-optimized PT3 antibody light chain variable region, a light chain constant region, and a human growth hormone polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2018 (TAU_ITR29) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody heavy chain signal sequence, a codon-optimized (Bioinformatics) PT3 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, an IPN002 antibody light chain signal sequence, a codon-optimized PT3 antibody light chain variable region, a light chain constant region, and a human growth hormone polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2019 (TAU_ITR30) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promotcr, an el exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody heavy chain signal sequence, a codon-optimized (NUS) PT3 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, an IPN002 antibody light chain signal sequence, a codon-optimized PT3 antibody light chain variable region, a light chain constant region, and a human growth hormone polyadenylation sequence.

TABLE 24 Sequence Regions in ITR to ITR Sequences TAU_ITR31 TAU_ITR32 TAU_ITR33 TAU_ITR34 TAU_ITR35 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO (SEQ ID NO: 2020) 2021) 2022) 2023) 2024) Region Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length ID NO length 5′ ITR 2077 141 2077 141 2077 141 2077 141 2077 141 Promoter 2084 654 2084 654 2084 654 2084 654 2084 654 Exon 2090 134 2090 134 2090 134 2090 134 2090 134 Intron 2095 32 2095 32 2095 32 2095 32 2095 32 Intron 2097 347 2097 347 2097 347 2097 347 2097 347 Exon 2093 53 2093 53 2093 53 2093 53 2093 53 Signal 1740 57 1740 57 1740 57 1740 57 1740 57 VH 1857 354 1853 354 1855 354 1851 354 1858 354 Constant 1742 969 1742 969 1742 969 1742 969 1742 969 Linker 1724 12 1724 12 1724 12 1724 12 1724 12 Linker 1726 54 1726 54 1726 54 1726 54 1726 54 Signal 1861 57 1861 57 1861 57 1861 57 1861 57 VL 1978 321 1974 321 1976 321 1972 321 1979 321 Constant 1864 321 1864 321 1864 321 1864 321 1864 321 Poly A 2123 477 2123 477 2123 477 2123 477 2123 477 3′ ITR 2079 141 2079 141 2079 141 2079 141 2079 141

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2020 (TAU_ITR31) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody heavy chain signal sequence, a codon-optimized (NUS2) PT3 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, an IPN002 antibody light chain signal sequence, a codon-optimized PT3 antibody light chain variable region, a light chain constant region, and a human growth hormone polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2021 (TAU_ITR32) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody heavy chain signal sequence, a codon-optimized (GeneInfinity) PT3 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, an IPN002 antibody light chain signal sequence, a codon-optimized PT3 antibody light chain variable region, a light chain constant region, and a human growth hormone polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2022 (TAU_ITR33) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody heavy chain signal sequence, a codon-optimized (IDT) PT3 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, an IPN002 antibody light chain signal sequence, a codon-optimized PT3 antibody light chain variable region, a light chain constant region, and a human growth hormone polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2023 (TAU_ITR34) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody heavy chain signal sequence, a codon-optimized (Bioinformatics 2) PT3 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, an IPN002 antibody light chain signal sequence, a codon-optimized PT3 antibody light chain variable region, a light chain constant region, and a human growth hormone polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2024 (TAU_ITR35) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, an IPN002 antibody heavy chain signal sequence, a codon-optimized (NUS3) PT3 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, an IPN002 antibody light chain signal sequence, a codon-optimized PT3 antibody light chain variable region, a light chain constant region, and a human growth hormone polyadenylation sequence.

TABLE 25 Sequence Regions in ITR to ITR Sequences TAU_ITR36 TAU_ITR37 TAU_ITR38 TAU_ITR39 TAU_ITR40 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2025) 2026) 2027) 2028) 2029) Region Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length ID NO length 5′ ITR 2077 141 2077 141 2077 141 2077 141 2077 141 CAG 2080 1715 2080 1715 2080 1715 2080 1715 2080 1715 promoter CMVie 2081 299 2081 299 2081 299 2081 299 2081 299 CBA min. 2082 283 2082 283 2082 283 2082 283 2082 283 Signal 1741 57 2106 84 2106 84 1741 57 1741 57 VH 1839 351 1839 351 1839 351 1839 351 1839 351 Linker 1730 45 1730 45 1730 45 1730 45 1730 45 VL 1957 339 1957 339 1957 339 1957 339 1957 339 Tag 2118 27 2119 21 2121 18 2118 27 2121 18 Poly A 2122 127 2123 477 2123 477 2123 477 2123 477 Filler 2125 1153 2126 1240 2126 1240 2126 1240 2126 1240 3′ ITR 2079 141 2079 141 2079 141 2079 141 2079 141

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2025 (TAU_ITR36) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a PHF1 antibody heavy chain signal sequence, a PHF1 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody light chain variable region, an HA tag, a rabbit globin polyadenylation signal sequence and a human albumin derived filler sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2026 (TAU_ITR37) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a human growth hormone-2 signal sequence, a PHF1 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody light chain variable region, an SEKDEL tag (“SEKDEL” disclosed as SEQ ID NO: 4546), a human growth hormone polyadenylation signal sequence and a human albumin derived filler sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2027 (TAU_ITR38) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a human growth hormone-2 signal sequence, a PHF1 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody light chain variable region, a His tag, a human growth hormone polyadenylation signal sequence and a human albumin derived filler sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2028 (TAU_ITR39) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a PHF1 antibody heavy chain signal sequence, a PHF1 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody light chain variable region, an HA tag, a human growth hormone polyadenylation signal sequence and a human albumin derived filler sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2029 (TAU_ITR40) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a PHF1 antibody heavy chain signal sequence, a PHF1 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody light chain variable region, a His tag, a human growth hormone polyadenylation signal sequence and a human albumin derived filler sequence.

TABLE 26 Sequence Regions in ITR to ITR Sequences TAU_ITR41 TAU_ITR42 TAU_ITR43 TAU_ITR44 TAU_ITR45 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2030) 2031) 2032) 2033) 2034) Region Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length ID NO length 5′ ITR 2077 141 2077 141 2077 141 2077 141 2077 141 CAG 2080 1715 2080 1715 2080 1715 2080 1715 2080 1715 promoter CMVie 2081 299 2081 299 2081 299 2081 299 2081 299 CBA min. 2082 283 2082 283 2082 283 2082 283 2082 283 Signal 2016 84 2106 84 1862 57 1862 57 1862 57 VL 1957 339 1957 339 1957 339 1957 339 1957 339 Linker 1730 45 1730 45 1730 45 1730 45 1730 45 VH 1839 351 1839 351 1839 351 1839 351 1839 351 Tag 2120 18 2121 18 2118 27 2121 18 2118 27 Poly A 2123 447 2123 477 2123 477 2123 477 2122 127 Filler 2126 1240 2126 1240 2126 1240 2126 1240 2125 1153 3′ ITR 2079 141 2079 141 2079 141 2079 141 2079 141

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2030 (TAU_ITR41) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a human growth hormone-2 signal sequence, a PHF1 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody heavy chain variable region, a SEKDEL tag (“SEKDEL” disclosed as SEQ ID NO: 4546), a human growth hormone polyadenylation signal sequence and a human albumin derived filler sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2031 (TAU_ITR42) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a human growth hormone-2 signal sequence, a PHF1 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody heavy chain variable region, a His tag, a human growth hormone polyadenylation signal sequence and a human albumin derived filler sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2032 (TAU_ITR43) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a PHF1 antibody light chain signal sequence, a PHF1 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody heavy chain variable region, an HA tag, a human growth hormone polyadenylation signal sequence and a human albumin derived filler sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2033 (TAU_ITR44) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a PHF1 antibody light chain signal sequence, a PHF1 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody heavy chain variable region, a His tag, a human growth hormone polyadenylation signal sequence and a human albumin derived filler sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2034 (TAU_ITR45) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a PHF1 antibody light chain signal sequence, a PHF1 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody heavy chain variable region, an HA tag, a rabbit globin polyadenylation signal sequence and a human albumin derived filler sequence.

TABLE 27 Sequence Regions in ITR to ITR Sequences TAU_ITR46 TAU_ITR47 TAU_ITR48 TAU_ITR49 TAU_ITR50 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2035) 2036) 2037) 2038) 2039) Region Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length ID NO length 5′ ITR 2077 141 2077 141 2077 141 2077 141 2077 141 CBA 2084 654 2084 654 2084 654 2084 654 2084 654 promoter Exon 2090 134 2092 59 2091 102 2090 134 2090 134 Intron 2095 32 2095 32 2096 15 2096 15 2095 32 Intron 2099 73 2098 168 2102 53 2102 53 2100 73 Exon 2093 53 2093 53 2093 53 2093 53 2093 53 Signal 1741 57 1741 57 1741 57 1741 57 1741 57 VH 1839 351 1839 351 1839 351 1839 351 1839 351 Linker 1730 45 1730 45 1730 45 1730 45 1730 45 VL 1957 339 1957 339 1957 339 1957 339 1957 339 Tag 2118 27 2118 27 2118 27 2118 27 2118 27 Poly A 2122 127 2122 127 2122 127 2122 127 2122 127 3′ ITR 2079 141 2079 141 2079 141 2079 141 2079 141

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2035 (TAU_ITR46) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, a PHF1 antibody heavy chain signal sequence, a PHF1 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2036 (TAU_ITR47) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, a PHF1 antibody heavy chain signal sequence, a PHF1 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2037 (TAU_ITR48) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, a PHF1 antibody heavy chain signal sequence, a PHF1 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2038 (TAU_ITR49) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, a PHF1 antibody heavy chain signal sequence, a PHF1 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2039 (TAU_ITR50) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, a PHF1 antibody heavy chain signal sequence, a PHF1 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

TABLE 28 Sequence Regions in ITR to ITR Sequences TAU_ITR51 TAU_ITR52 TAU_ITR53 TAU_ITR54 TAU_ITR55 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2040) 2041) 2042) 2043) 2044) Region Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length ID NO length 5′ ITR 2077 141 2077 141 2077 141 2077 141 2077 141 CBA 2084 654 2084 654 2084 654 2084 654 2084 654 promoter Exon 2092 59 2090 134 2090 134 — — — — Intron 2095 32 2095 32 2095 32 — — 2103 172 Intron 2098 168 2097 347 2097 347 — — — — Exon 2093 53 2093 53 2093 53 — — — — Signal 1862 57 1862 57 1862 57 1862  57 1862  57 VL 1957 339 1957 339 1957 339 1957 339 1957 339 Linker 1730 45 1730 45 1730 45 1730  45 1736  45 VH 1839 351 1839 351 1839 351 1839 351 1839 351 Tag 2118 27 2118 27 2118 27 2118  27 2118  27 Poly A 2122 127 2122 127 2122 127 2122 127 2122 127 Filler — — — — 2125 1153 — — — — 3′ ITR 2079 141 2079 141 2079 141 2079 141 2079 141

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2040 (TAU_ITR51) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, a PHF1 antibody light chain signal sequence, a PHF1 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2041 (TAU_ITR52) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, a PHF1 antibody light chain signal sequence, a PHF1 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2042 (TAU_ITR53) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, a PHF1 antibody light chain signal sequence, a PHF1 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody heavy chain variable region, an HA tag, a rabbit globin polyadenylation signal sequence and a human albumin derived filler sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2043 (TAU_ITR54) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, a PHF1 antibody light chain signal sequence, a PHF1 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2044 (TAU_ITR55) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an SV40 intron, a PHF1 antibody light chain signal sequence, a PHF1 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

TABLE 29 Sequence Regions in ITR to ITR Sequences TAU_ITR56 TAU_ITR57 TAU_ITR58 TAU_ITR59 TAU_ITR60 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2045) 2046) 2047) 2048) 2049) Region Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length ID NO length 5′ ITR 2077 141 2077 141 2077 141 2077 141 2077 141 CBA 2084 654 2084 654 2084 654 2084 654 2084 654 promoter Exon 2090 134 2090 134 2090 134 — — — — Intron 2095 32 2095 32 2095 32 — — 2103 172 Intron 2097 347 2097 347 2101 73 — — — — Exon 2093 53 2093 53 2093 53 — — — — Signal 1741 57 1741 57 1741 57 1741  57 1741  57 VH 1839 351 1839 351 1839 351 1839 351 1839 351 Linker 1730 45 1730 45 1730 45 1730  45 1730  45 VL 1957 339 1957 339 1957 339 1957 339 1957 339 Tag 2118 27 2118 27 2118 27 2118  27 2118  27 Poly A 2122 127 2122 127 2122 127 2122 127 2122 127 Filler 2125 1153 — — — — — — — — 3′ ITR 2079 141 2079 141 2079 141 2079 141 2079 141

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2045 (TAU_ITR56) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, a PHF1 antibody heavy chain signal sequence, a PHF1 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody light chain variable region, an HA tag, a rabbit globin polyadenylation signal sequence and a human albumin derived filler sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2046 (TAU_ITR57) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, a PHF1 antibody heavy chain signal sequence, a PHF1 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2047 (TAU_ITR58) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, a PHF11 antibody heavy chain signal sequence, a PHF1 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2048 (TAU_ITR59) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, a PHF1 antibody heavy chain signal sequence, a PHF1 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2049 (TAU_ITR60) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an SV40 intron, a PHF1 antibody heavy chain signal sequence, a PHF1 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

TABLE 30 Sequence Regions in ITR to ITR Sequences TAU_ITR61 TAU_ITR62 TAU_ITR63 TAU_ITR64 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2050) 2051) 2052) 2053) Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length 5′ ITR 2077 141 2077 141 2077 141 2077 141 CBA 2084 654 2084 654 2084 654 2084 654 promoter Exon 2090 134 2090 134 2090 134 2090 134 Intron 2095 32 2095 32 2095 32 2095 32 Intron 2097 347 2097 347 2097 347 2097 347 Exon 2093 53 2093 53 2093 53 2093 53 Signal 1741 57 1741 57 1741 57 1741 57 VH1 1839 351 1839 351 1839 351 1839 351 Linker 1730 45 1730 45 1730 45 1730 45 VL 1957 339 1957 339 1957 339 1957 339 Tag — — — — 2118 27 2118 27 Linker — — — — 1724 12 1724 12 Linker 1729 18 1729 18 1726 54 1726 54 Signal 1741 57 1741 57 1741 57 1741 57 VH 1839 351 1839 351 1839 351 1839 351 Linker 1730 45 1730 45 1730 45 1730 45 VL 1957 339 1957 339 1957 339 1957 339 Tag — — — — 2118 27 — — Linker — — — — 1724 12 — — Linker 1729 18 — — 1726 54 — — Signal — — — — 1741 57 — — VH 1839 351 — — 1839 351 — — Linker 1730 45 — — 1730 45 — — VL 1957 339 — — 1957 339 — — Tag 2118 27 2118 27 2118 27 2118 27 Poly A 2122 127 2122 127 2122 127 2122 127 3′ ITR 2079 141 2079 141 2079 141 2079 141

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2050 (TAU_ITR61) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promotcr, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, a PHF1 antibody heavy chain signal sequence, a PHF1 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody light chain variable region, a G4S linker (“G4S” disclosed as SEQ ID NO: 4535), a second PHF1 antibody heavy chain signal sequence, a second PHF1 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a second PHF1 antibody light chain variable region, a G4S linker (“G4S” disclosed as SEQ ID NO: 4535), a third PHF1 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a third PHF1 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2051 (TAU_ITR62) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, a PHF1 antibody heavy chain signal sequence, a PHF1 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody light chain variable region, a G4S linker (“G4S” disclosed as SEQ ID NO: 4535), a second PHF1 antibody heavy chain signal sequence, a second PHF1 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a second PHF1 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2052 (TAU_ITR63) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, a PHF1 antibody heavy chain signal sequence, a PHF1 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody light chain variable region, an HA tag, a furin cleavage site, a T2A linker, a second PHF1 antibody heavy chain signal sequence, a second PHF1 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a second PHF1 antibody light chain variable region, a second HA tag, a second furin cleavage site, a second T2A linker, a third PHF1 antibody heavy chain signal sequence, a third PHF1 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a third PHF1 antibody light chain variable region, a third HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2053 (TAU_ITR64) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, a PHF1 antibody heavy chain signal sequence, a PHF1 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody light chain variable region, an HA tag, a furin cleavage site, a T2A linker, a second PHF1 antibody heavy chain signal sequence, a second PHF1 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a second PHF1 antibody light chain variable region, a second HA tag, and a rabbit globin polyadenylation signal sequence.

TABLE 31 Sequence Regions in ITR to ITR Sequences TAU_ITR65 TAU_ITR66 TAU_ITR67 TAU_ITR68 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2054) 2055) 2056) 2057) Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length 5′ ITR 2077 141 2077 141 2077 141 2077 141 CBA 2084 654 2084 654 2084 654 2084 654 promoter Exon 2090 134 2090 134 2090 134 2090 134 Intron 2095 32 2095 32 2095 32 2095 32 Intron 2097 347 2097 347 2097 347 2097 347 Exon 2093 53 2093 53 2093 53 2093 53 Signal 1862 57 1862 57 1862 57 1862 57 VL 1956 339 1956 339 1956 339 1956 339 Linker 1730 45 1730 45 1730 45 1730 45 VH 1839 351 1839 351 1839 351 1839 351 Tag — — — — 2118 27 2118 27 Linker — — — — 1724 12 1724 12 Linker 1729 18 — — 1726 54 1726 54 Signal — — — — 1862 57 1862 57 VL 1956 339 1956 339 1956 339 1956 339 Linker 1730 45 1730 45 1730 45 1730 45 VH 1839 351 1839 351 1839 351 1839 351 Tag — — — — 2118 27 — — Linker — — — — 1724 12 — — Linker 1729 18 — 1726 54 — — Signal — — — — 1862 57 — — VL 1956 339 — — 1956 339 — — Linker 1730 45 — — 1730 45 — — VH 1839 351 — — 1839 351 — — Tag 2118 27 2118 — 2118 27 2118 27 Poly A 2122 127 2122 127 2122 127 2122 127 3′ ITR 2079 141 2079 141 2079 141 2079 141

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2054 (TAU_ITR65) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, a PHF1 antibody light chain signal sequence, a PHF1 antibody light chain variable region, a (G4S).3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody heavy chain variable region, a G4S linker (“G4S” disclosed as SEQ ID NO: 4535), a second PHF1 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a second PHF1 antibody heavy chain variable region, a G4S linker (“G4S” disclosed as SEQ ID NO: 4535), a third PHF1 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a third PHF1 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2055 (TAU_ITR66) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, a PHF1 antibody light chain signal sequence, a PHF1 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody heavy chain variable region, a second PHF1 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a second PHF1 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2056 (TAU_ITR67) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, a PHF1 antibody light chain signal sequence, a PHF1 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody heavy chain variable region, an HA tag, a furin cleavage site, a T2A linker, a second PHF1 antibody light chain signal sequence, a second PHF1 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a second PHF1 antibody heavy chain variable region, a second HA tag, a second furin cleavage site, a second T2A linker, a third PHF1 antibody light chain signal sequence, a third PHF1 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a third PHF1 antibody heavy chain variable region, a third HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2057 (TAU_ITR68) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, a PHF1 antibody light chain signal sequence, a PHF1 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a PHF1 antibody heavy chain variable region, an HA tag, a furin cleavage site, a T2A linker, a second PHF1 antibody light chain signal sequence, a second PHF1 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a second PHF1 antibody heavy chain variable region, a second HA tag, and a rabbit globin polyadenylation signal sequence.

TABLE 32 Sequence Regions in ITR to ITR Sequences TAU_ITR69 TAU_ITR70 TAU_ITR71 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2058) 2059) 2060) Region Region Region Sequence SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 Promoter 2087 382 2087 382 2085 699 Promoter 2083 260 2083 260 — — Exon 2090 134 2090 134 — — Intron 2095  32 2095  32 2103 172 Intron 2097 347 2097 347 — — Exon 2093  53 2093  53 — — VH 1838 1377  — — — — VL — — 1962 714 1962 714 Linker 1727  75 1727  75 1727  75 VL 1962 714 — — — — VH — — 1838 1377  1838 1377  Poly A 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2058 (TAU_ITR69) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a CB promoter, an ie1 exon 1 region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, a PHF1 antibody heavy chain region, an F2A linker, a PHF1 antibody light chain region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2059 (TAU_ITR70) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a CB promoter, an ie1 exon region, an ie1 intron 1 region, a human beta-globin intron region, a human beta-globin exon region, a PHF1 antibody light chain variable region, an F2A linker, a PHF1 antibody heavy chain variable region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2060 (TAU_ITR71) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, an SV40 intron, a PHF1 antibody light chain variable region, an F2A linker, a PHF1 antibody heavy chain variable region, and a rabbit globin polyadenylation signal sequence.

TABLE 33 Sequence Regions in ITR to ITR Sequences TAU_ITR72 TAU_ITR73 TAU_ITR74 TAU_ITR75 TAU_ITR76 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2061) 2062) 2063) 2064) 2065) Region Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 2076 130 CMVie 2087 382 2087 382 2087 382 2087 382 2087 382 Promoter 2083 260 2083 260 2083 260 2083 260 2083 260 Intron 2103 172 2103 172 2103 172 2103 172 2103 172 VH 1832 1374 1832 1374 1832 1374 1832 1374  1832 1374 Linker 1725 12 1725 12 — — — — — — Linker 1727 75 1728 66 1727 75 1732 609 1728 66 VL 1950 714 1950 714 1950 714 1950 714 1950 714 Poly A 2122 127 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2061 (TAU_ITR72) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a CB promoter, an SV40 intron, an MC1 antibody heavy chain variable region, a furin cleavage site, an F2A linker, an MC1 antibody light chain variable region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2062 (TAU_ITR73) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a CB promoter, an SV40 intron, an MC1 antibody heavy chain variable region, a furin cleavage site, a P2A linker, an MC1 antibody light chain variable region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2063 (TAU_ITR74) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a CB promoter, an SV40 intron, an MC1 antibody heavy chain variable region, an F2A linker, an MC1 antibody light chain variable region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2064 (TAU_ITR75) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a CB promoter, an SV40 intron, an MC1 antibody heavy chain variable region, an IRES linker, an MC1 antibody light chain variable region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2065 (TAU_ITR76) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a CB promoter, an SV40 intron, an MC1 antibody heavy chain variable region, a P2A linker, an MC1 antibody light chain variable region, and a rabbit globin polyadenylation signal sequence.

TABLE 34 Sequence Regions in ITR to ITR Sequences TAU_ITR77 TAU_ITR85 (SEQ ID NO: 2066) (SEQ ID NO: 2074) Sequence Region Region Region Region Regions SEQ ID NO SEQ ID NO length length 5′ ITR 2076 130 2076 130 CMVie 2087 382 2087 382 Promoter 2083 260 2083 260 Intron 2103 172 2103 172 VH 1820 1377 1838 1377 Linker 1725 12 1725 12 Linker 1727 75 1727 75 VL 1940 714 1962 714 PolyA 2122 127 2122 127 3′ ITR 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2066 (TAU_ITR77) which comprises a 5 inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a CB promoter, an SV40 intron, an IPN002 antibody heavy chain variable region, a furin cleavage site, an F2A linker, an IPN002 antibody light chain variable region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2074 (TAU_ITR85) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a ITR sequence region, a CMVie region, a CB promoter, an SV40 intron, an PHF1 antibody heavy chain variable region, a furin cleavage site, an F2A linker, an PHF1 antibody light chain variable region, and a rabbit globin polyadenylation signal sequence.

TABLE 35 Sequence Regions in ITR to ITR Sequences TAU_ITR78 TAU_ITR79 TAU_ITR80 TAU_ITR81 TAU_ITR82 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2067) 2068) 2069) 2070) 2071) Region Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 2076 130 CMVie 2087 382 2087 382 2087 382 2087 382 2087 382 Promoter 2083 260 2083 260 2083 260 2083 260 2083 260 SV40 2103 172 2103 172 2103 172 2103 172 2103 172 VL 1950 714 1950 714 1950 714 1950 714 1950 714 Linker 1725 12 — — — — — — — — Linker 1727 75 1727 75 1732 609 1731 75 1728 66 VH 1832 1374 1832 1374 1832 1374  1832 1374 1832 1374 Poly A 2122 127 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2067 (TAU_ITR78) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a CB promoter, an SV40 intron, an MC1 antibody light chain variable region, a furin cleavage site, an F2A linker, an MC1 antibody heavy chain variable region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2068 (TAU_ITR79) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a CB promoter, an SV40 intron, an MC1 antibody light chain variable region, an F2A linker, an MC1 antibody heavy chain variable region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2069 (TAU_ITR80) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a CB promoter, an SV40 intron, an MC1 antibody light chain variable region, an IRES linker, an MC1 antibody heavy chain variable region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2070 (TAU_ITR81) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a CB promoter, an SV40 intron, an MC1 antibody light chain variable region, a (G4S)5 linker (“(G4S)5” disclosed as SEQ ID NO: 4538), an MC1 antibody heavy chain variable region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2071 (TAU_ITR82) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a CB promoter, an SV40 intron, an MC1 antibody light chain variable region, an P2A linker, an MC1 antibody heavy chain variable region, and a rabbit globin polyadenylation signal sequence.

TABLE 36 Sequence Regions in ITR to ITR Sequences TAU_ITR83 TAU_ITR84 TAU_ITR86 (SEQ ID NO: (SEQ IDNO: (SEQ ID NO: 2072) 2073) 2075) Region Region Region Sequence SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 CMVie 2087 382 2087 382 2087 382 Promoter 2083 260 2083 260 2083 260 Intron 2103 172 2103 172 2103 172 VL 1950 714 1940 714 1962 714 Linker 1725 12 — — — — Linker 1728 66 1727 75 1727 75 VH 1832 1374 1820 1377 1838 1377 Poly A 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2072 (TAU_ITR83) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a CB promoter, an SV40 intron, an MC1 antibody light chain variable region, a furin cleavage site, a P2A linker, an MC1 antibody heavy chain variable region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2073 (TAU_ITR84) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a CB promoter, an SV40 intron, an IPN002 antibody light chain variable region, an F2A linker, an IPN002 antibody heavy chain variable region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2075 (TAU_ITR86) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a CB promoter, an SV40 intron, a PHF1 antibody light chain variable region, an F2A linker, a PHF1 antibody heavy chain variable region, and a rabbit globin polyadenylation signal sequence.

TABLE 37 Sequence Regions in ITR to ITR Sequences TAU_ITR89 TAU_ITR97 TAU_ITR218 TAU_ITR220 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2139) 2147) 2290) 2292) Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 CAG 2080 1715 2080 1715 2080 1715 2080 1715 promoter CMVie 2081 299 2081 299 2081 299 2081 299 CBA min. 2082 283 2082 283 2082 283 2082 283 Signal 1740 57 1740 57 1740 57 1740 57 VH 1809 345 1809 345 1809 345 1809 345 Constant 1742 969 1742 969 2242 309 2243 291 Linker 1725 12 1724 12 1724 12 1724 12 Linker 1727 75 1726 54 1726 54 1726 54 Signal 1861 57 1861 57 1861 57 1861 57 VL 1926 321 1926 321 1926 321 1926 321 Constant 1864 321 1864 321 1864 321 1864 321 Poly A 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2139 (TAU_ITR89) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a F2A linker, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2147 (TAU_ITR97) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2290 (TAU_ITR218) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2290 (TAU_ITR220) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

TABLE 38 Sequence Regions in ITR to ITR Sequences TAU_ITR217 TAU_ITR126 (SEQ ID NO: 2289) (SEQ ID NO: 2176) Sequence Region SEQ Region Region SEQ Region Regions ID NO length ID NO length 5′ ITR 2076 130 2076 130 CAG promoter 2080 1715 2080 1715 CMVie 2081 299 2081 299 CBA min. 2082 283 2082 283 Signal 1740 57 1740 57 VH 1809 345 1821 351 Constant 2242 309 2242 309 Linker 2244 198 2244 198 Linker 1724 12 1724 12 Linker 1726 54 1726 54 Signal 1861 57 1861 57 VL 1926 321 1939 336 Constant 1864 321 1864 321 PolyA 2122 127 2122 127 3′ ITR 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2289 (TAU_ITR217) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, a hinge region, a furin cleavage site, a T2A linker, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2289 (TAU_ITR217) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, a hinge region, a furin cleavage site, a T2A linker, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

TABLE 39 Sequence Regions in ITR to ITR Sequences TAU_ITR222 TAU_ITR223 TAU_ITR224 TAU_ITR221 TAU_ITR151 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2294) 2295) 2296) 2293) 2201) Region Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 2076 130 CAG 2080 1715 2080 1715 2080 1715 2080 1715 2080 1715 promoter CMVie 2081 299 2081 299 2081 299 2081 299 2081 299 CBA min. 2082 283 2082 283 2082 283 2082 283 2082 283 Signal 1861 57 1861 57 1861 57 1861 57 1861 57 VL 1926 321 1926 321 1926 321 1926 321 1939 336 Linker 2247 45 2250 75 2253 120 2245 15 2246 30 VH 1809 345 1809 345 1809 345 1809 345 1821 351 Tag 2118 27 2118 27 2118 27 2118 27 2118 27 Poly A 2122 127 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2294 (TAU_ITR222) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal sequence, a C10.2 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a C10.2 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2295 (TAU_ITR223) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal sequence, a C10.2 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a C10.2 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2296 (TAU_ITR224) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal sequence, a C10.2 antibody light chain variable region, a (G4S)8 linker (“(G4S)8” disclosed as SEQ ID NO: 4542), a C10.2 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2293 (TAU_ITR221) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal sequence, a C10.2 antibody light chain variable region, a G4S linker (“G4S” disclosed as SEQ ID NO: 4535), a C10.2 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2201 (TAU_ITR151) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal sequence, an IPN002 antibody light chain variable region, a (G4S)2 linker (“(G4S)2” disclosed as SEQ ID NO: 4539), an IPN002 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

TABLE 40 Sequence Regions in ITR to ITR Sequences TAU_ITR93 TAU_ITR100 TAU_ITR219 TAU_ITR130 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2143) 2150) 2291) 2180) Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 CAG 2080 1715 2080 1715 2080 1715 2080 1715 promoter CMVie 2081 299 2081 299 2081 299 2081 299 CBA mm. 2082 283 2082 283 2082 283 2082 283 Signal 1861 57 1861 57 1861 57 1861 57 VL 1926 321 1926 321 1926 321 1939 336 Constant 1864 321 1864 321 1864 321 1864 321 Linker 1727 75 1726 54 1726 54 1726 54 Signal 1740 57 1740 57 1740 57 1740 57 VH 1809 345 1809 345 1809 345 1821 351 Constant 1742 969 1743 972 2242 309 2242 309 Poly A 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2143 (TAU_ITR93) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, a F2A linker, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2150 (TAU_ITR100) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, a T2A linker, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2291 (TAU_ITR219) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, a T2A linker, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2180 (TAU_ITR130) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal sequence, an IPN002 antibody light chain variable region, a light chain constant region, a T2A linker, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a heavy chain constant region, and a rabbit globin polyadenylation signal sequence.

TABLE 41 Sequence Regions in ITR to ITR Sequences TAU_ITR90 TAU_ITR98 TAU_ITR226 TAU_ITR228 TAU_ITR198 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2140) 2148) 2298) 2300) 2270) Region Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 2076 130 Promoter 2085 699 2085 699 2085 699 2085 699 2085 699 Intron 2240 566 2240 566 2240 566 2240 566 2240 566 Signal 1740 57 1740 57 1740 57 1740 57 1740 57 VH 1809 345 1809 345 1809 345 1809 345 1821 351 Constant 1742 969 1742 969 2242 309 2243 291 2242 309 Linker 1725 12 1724 12 1724 12 1724 12 1724 12 Linker 1727 75 1726 54 1726 54 1726 54 1726 54 Signal 1861 57 1861 57 1861 57 1861 57 1861 57 VL 1926 321 1926 321 1926 321 1926 321 1939 336 Constant 1864 321 1864 321 1864 321 1864 321 1864 321 Poly A 2122 127 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2140 (TAU_ITR90) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a F2A linker, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2148 (TAU_ITR98) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2298 (TAU_ITR226) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2300 (TAU_ITR228) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2270 (TAU_ITR198) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, a light chain signal sequence, an IPN002 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

TABLE 42 Sequence Regions in ITR to ITR Sequences TAU_ITR225 TAU_ITR197 TAU_ITR207 TAU_ITR122 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2297) 2269) 2279) 2172) Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 Promoter 2085 699 2085 699 2086 557 2239 380 Intron 2240 566 2240 566 2240 566 2240 566 Signal 1740 57 1740 57 1740 57 2241 57 VH 1809 345 1821 351 1821 351 1821 351 Constant 2242 309 2242 309 2242 309 2242 309 Linker 2244 198 2244 198 2244 198 2244 198 Linker 1724 12 1724 12 1724 12 1724 12 Linker 1726 54 1726 54 1726 54 1726 54 Signal 1861 57 1861 57 1861 57 1861 57 VL 1926 321 1939 336 1939 336 1939 336 Constant 1864 321 1864 321 1864 321 1864 321 Poly A 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2297 (TAU_ITR225) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, a hinge region, a furin cleavage site, a T2A linker, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2269 (TAU_ITR197) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a heavy chain constant region, a hinge region, a furin cleavage site, a T2A linker, a light chain signal sequence, an IPN002 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2279 (TAU_ITR207) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a hSYN promoter, a human beta-globin intron region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a heavy chain constant region, a hinge region, a furin cleavage site, a T2A linker, a light chain signal sequence, an IPN002 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2172 (TAU_ITR122) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a human beta-globin intron region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a heavy chain constant region, a hinge region, a furin cleavage site, a T2A linker, a light chain signal sequence, an IPN002 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

TABLE 43 Sequence Regions in ITR to ITR Sequences TAU_ITR230 TAU_ITR231 TAU_ITR232 TAU_ITR204 TAU_ITR205 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2302) 2303) 2304) 2276) 2277) Region Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 2076 130 Promoter 2085 699 2085 699 2085 699 2085 699 2085 699 Intron 2240 566 2240 566 2240 566 2240 566 2240 566 Signal 1861 57 1861 57 1861 57 1861 57 1861 57 VL 1926 321 1926 321 1926 321 1939 336 1939 336 Linker 2247 45 2250 75 2253 120 2245 15 2247 45 VH 1809 345 1809 345 1809 345 1821 351 1821 351 Tag 2118 27 2118 27 2118 27 2118 27 2118 27 Poly A 2122 127 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2302 (TAU_ITR230) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a light chain signal sequence, a C10.2 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a C10.2 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2303 (TAU_ITR231) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a light chain signal sequence, a C10.2 antibody light chain variable region, a (G4S)5 linker (“(G4S)5” disclosed as SEQ ID NO: 4538), a C10.2 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2304 (TAU_ITR232) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a light chain signal sequence, a C10.2 antibody light chain variable region, a (G4S)8 linker (“G4S)8” disclosed as SEQ ID NO: 4542), a C10.2 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2276 (TAU_ITR204) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a light chain signal sequence, an IPN002 antibody light chain variable region, a G4S linker (“G4S” disclosed as SEQ ID NO: 4535), an IPN002 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2277 (TAU_ITR205) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a light chain signal sequence, an IPN002 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), an IPN002 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

TABLE 44 Sequence Regions in ITR to ITR Sequences TAU_ITR94 TAU_ITR101 TAU_ ITR227 TAU_ITR95 TAU_ITR102 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2144) 2151) 2299) 2145) 2152) Region Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 2076 130 Promoter 2085 699 2085 699 2085 699 2086 557 2086 557 Intron 2240 566 2240 566 2240 566 2240 566 2240 566 Signal 1861 57 1861 57 1861 57 1861 57 1861 57 VL 1926 321 1926 321 1926 321 1926 321 1926 321 Constant 1864 321 1864 321 1864 321 1864 321 1864 321 Linker 1727 75 1726 54 1726 54 1727 75 1726 54 Signal 1740 57 1740 57 1740 57 1740 57 1740 57 VH 1809 345 1809 345 1809 345 1809 345 1809 345 Constant 1742 969 1743 972 2242 309 1742 969 1743 972 Poly A 2122 127 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2144 (TAU_ITR94) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, a F2A linker, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2151 (TAU_ITR101) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, a T2A linker, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2299 (TAU_ITR227) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, a T2A linker, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2145 (TAU_ITR95) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a hSYN promoter, a human beta-globin intron region, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, a F2A linker, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2152 (TAU_ITR102) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a hSYN promoter, a human beta-globin intron region, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, a T2A linker, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, and a rabbit globin polyadenylation signal sequence.

TABLE 45 Sequence Regions in ITR to ITR Sequences TAU_ITR229 TAU_ITR238 TAU_ITR239 TAU_ITR240 TAU_ITR237 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2301) 2310) 2311) 2312) 2309) Region Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 2076 130 Promoter 2085 699 2086 557 2086 557 2086 557 2086 557 Intron 2240 566 2240 566 2240 566 2240 566 2240 566 Signal 1861 57 1861 57 1861 57 1861 57 1861 57 VL 1926 321 1926 321 1926 321 1926 321 1926 321 Linker 2245 15 2247 45 2250 75 2253 120 2245 15 VH 1809 345 1809 345 1809 345 1809 345 1809 345 Tag 2118 27 2118 27 2118 27 2118 27 2118 27 Poly A 2122 127 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2301 (TAU_ITR229) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a light chain signal sequence, a C10.2 antibody light chain variable region, a G4S linker (“G4S” disclosed as SEQ ID NO: 4535), a C10.2 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2310 (TAU_ITR238) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a hSYN promoter, a human beta-globin intron region, a light chain signal sequence, a C10.2 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), a C10.2 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2311 (TAU_ITR239) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a hSYN promoter, a human beta-globin intron region, a light chain signal sequence, a C10.2 antibody light chain variable region, a (G4S)5 linker (“(G4S)5” disclosed as SEQ ID NO: 4538), a C10.2 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2312 (TAU_ITR240) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a hSYN promoter, a human beta-globin intron region, a light chain signal sequence, a C10.2 antibody light chain variable region, a (G4S)8 linker (“(G4S)8” disclosed as SEQ ID NO: 4542), a C10.2 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2309 (TAU_ITR237) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a hSYN promoter, a human beta-globin intron region, a light chain signal sequence, a C10.2 antibody light chain variable region, a G4S linker (“G4S” disclosed as SEQ ID NO: 4535), a C10.2 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

TABLE 46 Sequence Regions in ITR to ITR Sequences TAU_ITR91 TAU_ITR99 TAU_ITR234 TAU_ITR236 TAU_ITR208 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2141) 2149) 2306) 2308) 2280) Region Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 2076 130 Promoter 2086 557 2086 557 2086 557 2086 557 2086 557 Intron 2240 566 2240 566 2240 566 2240 566 2240 566 Signal 1740 57 1740 57 1740 57 1740 57 1740 57 VH 1809 345 1809 345 1809 345 1809 345 1821 351 Constant 1742 969 1742 969 2242 309 2243 291 2242 309 Linker 1725 12 1724 12 1724 12 1724 12 1724 12 Linker 1727 75 1726 54 1726 54 1726 54 1726 54 Signal 1861 57 1861 57 1861 57 1861 57 1861 57 VL 1926 321 1926 321 1926 321 1926 321 1939 336 Constant 1864 321 1864 321 1864 321 1864 321 1864 321 Poly A 2122 127 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2141 (TAU_ITR91) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a hSYN promoter, a human beta-globin intron region, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a F2A linker, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2149 (TAU_ITR99) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a hSYN promoter, a human beta-globin intron region, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2306 (TAU_ITR234) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a hSYN promoter, a human beta-globin intron region, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2308 (TAU_ITR236) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a hSYN promoter, a human beta-globin intron region, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2280 (TAU_ITR208) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a hSYN promoter, a human beta-globin intron region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, a light chain signal sequence, an IPN002 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

TABLE 47 Sequence Regions in ITR to ITR Sequences Sequence TAU_ITR233 (SEQ ID NO: 2305) Regions Region SEQ ID NO Region length 5′ ITR 2076 130 Promoter 2086 557 Intron 2240 566 Signal 1740 57 VH 1809 345 Constant 2242 309 Linker 2244 198 Linker 1724 12 Linker 1726 54 Signal 1861 57 VL 1926 321 Constant 1864 321 PolyA 2122 127 3′ ITR 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2305 (TAU_ITR233) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a hSYN promoter, a human beta-globin intron region, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, a hinge region, a furin cleavage site, a T2A linker, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

TABLE 48 Sequence Regions in ITR to ITR Sequences TAU_ITR235 TAU_ITR199 TAU_ITR209 TAU_ITR129 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2307) 2271) 2281) 2179) Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 Promoter 2086 557 2085 699 2086 557 2239 380 Intron 2240 566 2240 566 2240 566 2240 566 Signal 1861 57 1861 57 1861 57 1861 57 VL 1926 321 1939 336 1939 336 1939 336 Constant 1864 321 1864 321 1864 321 1864 321 Linker 1726 54 1726 54 1726 54 1726 54 Signal 1740 57 1740 57 1740 57 1740 57 VH 1809 345 1821 351 1821 351 1821 351 Constant 2242 309 2242 309 2242 309 2242 309 PolyA 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2307 (TAU_ITR235) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a hSYN promoter, a human beta-globin intron region, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, a T2A linker, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2271 (TAU_ITR199) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a light chain signal sequence, an IPN002 antibody light chain variable region, a light chain constant region, a T2A linker, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a heavy chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2281 (TAU_ITR209) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a hSYN promoter, a human beta-globin intron region, a light chain signal sequence, an IPN002 antibody light chain variable region, a light chain constant region, a T2A linker, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a heavy chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2179 (TAU_ITR129) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a human beta-globin intron region, a light chain signal sequence, an IPN002 antibody light chain variable region, a light chain constant region, a T2A linker, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a heavy chain constant region, and a rabbit globin polyadenylation signal sequence.

TABLE 49 Sequence Regions in ITR to ITR Sequences TAU_ITR88 TAU_ITR96 (SEQ ID NO: 2138) (SEQ ID NO: 2146) Sequence Region SEQ Region Region SEQ Region Regions ID NO length ID NO length 5′ ITR 2076 130 2076 130 Promoter 2239 380 2239 380 Promoter 2083 260 2083 260 Intron 2240 566 2240 566 Signal 1740 57 1740 57 VH 1809 345 1809 345 Constant 1742 969 1742 969 Linker 1725 12 1724 12 Linker 1727 75 1726 54 Signal 1861 57 1861 57 VL 1926 321 1926 321 Constant 1864 321 1864 321 PolyA 2122 127 2122 127 3′ ITR 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2138 (TAU_ITR88) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a CB promoter, a human beta-globin intron region, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, an F2A linker, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2146 (TAU_ITR96) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a CB promoter, a human beta-globin intron region, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, an T2A linker, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

TABLE 50 Sequence Regions in ITR to ITR Sequences Sequence TAU_ITR92 (SEQ ID NO: 2142) Regions Region SEQ ID NO Region length 5′ ITR 2076 130 Promoter 2239 380 Promoter 2083 260 Intron 2240 566 Signal 1861 57 VL 1926 321 Constant 1864 321 Linker 1727 75 Signal 1740 57 VH 1809 345 Constant 1742 969 PolyA 2122 127 3′ ITR 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2142 (TAU_ITR92) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a CB promoter, a human beta-globin intron region, a light chain signal sequence, a C10.2 antibody light chain variable region, a light chain constant region, an F2A linker, a heavy chain signal sequence, a C10.2 antibody heavy chain variable region, a heavy chain constant region, and a rabbit globin polyadenylation signal sequence.

TABLE 51 Sequence Regions in ITR to ITR Sequences TAU_ITR139 TAU_ITR140 TAU_ITR141 TAU_ITR142 TAU_ITR143 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2189) 2190) 2191) 2192) 2193) Region Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 2076 130 CAG 2080 1715 2080 1715 2080 1715 2080 1715 2080 1715 promoter CMVie 2081 299 2081 299 2081 299 2081 299 2081 299 CBA min. 2082 283 2082 283 2082 283 2082 283 2082 283 Signal 1740 57 1740 57 1740 57 1740 57 1740 57 VH 1821 351 1821 351 1821 351 1821 351 1821 351 Linker 1730 45 2254 60 2249 75 2251 90 2252 120 VL 1939 336 1939 336 1939 336 1939 336 1939 336 Tag 2118 27 2118 27 2118 27 2118 27 2118 27 PolyA 2122 127 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 136 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2189 (TAU_ITR139) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), an IPN002 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2190 (TAU_ITR140) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a (G4S)4 linker (“(G4S)4” disclosed as SEQ ID NO: 4540), an IPN002 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2191 (TAU_ITR141) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a (G4S)5 linker (“(G4S)5” disclosed as SEQ ID NO: 4538), an IPN002 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2192 (TAU_ITR142) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a (G4S)6 linker (“(G4S)4” disclosed as SEQ ID NO: 4541), an IPN002 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2193 (TAU_ITR143) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a (G4S)8 linker (“(G4S)8” disclosed as SEQ ID NO: 4542), an IPN002 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

TABLE 52 Sequence Regions in ITR to ITR Sequences Sequence TAU_ITR137 (SEQ ID NO: 2187) Regions Region SEQ ID NO Region length 5′ ITR 2076 130 CAG promoter 2080 1715 CMVie 2081 299 CBA min. 2082 283 Signal 1740 57 VH 1821 351 Linker 2245 15 VL 1939 336 Tag 2118 27 PolyA 2122 127 3′ ITR 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2187 (TAU_ITR137) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a G4S linker (“G4S” disclosed as SEQ ID NO: 4535), an IPN002 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

TABLE 53 Sequence Regions in ITR to ITR Sequences TAU_ITR125 TAU_ITR127 TAU_ITR128 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2175) 2177) 2178) Region Region Region Sequence SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 CAG 2080 1715 2080 1715 2080 1715 promoter CMVie 2081 299 2081 299 2081 299 CBA min. 2082 283 2082 283 2082 283 Signal 1740 57 1740 57 1740 57 VH 1821 351 1821 351 1821 351 Constant 2242 309 2243 291 2242 309 Linker 1724 12 1724 12 1724 12 Linker 1726 54 1726 54 1726 54 Signal 1861 57 1861 57 1861 57 VL 1939 336 1939 336 1939 336 Constant 1864 321 1864 321 1864 321 PolyA 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2175 (TAU_ITR125) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, a light chain signal sequence, an IPN002 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2177 (TAU_ITR127) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, a light chain signal sequence, an IPN002 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2178 (TAU_ITR128) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, a light chain signal sequence, an IPN002 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

TABLE 54 Sequence Regions in ITR to ITR Sequences Sequence TAU_ITR126 (SEQ ID NO: 2176) Regions Region SEQ ID NO Region length 5′ ITR 2076 130 CAG promoter 2080 1715 CMVie 2081 299 CBA min. 2082 283 Signal 1740 57 VH 1821 351 Constant 2242 309 Linker 2244 198 Linker 1724 12 Linker 1726 54 Signal 1861 57 VL 1939 336 Constant 1864 321 PolyA 2122 127 3′ ITR 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2176 (TAU_ITR126) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a heavy chain constant region, a hinge region, a furin cleavage site, a T2A linker, a light chain signal sequence, an IPN002 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

TABLE 55 Sequence Regions in ITR to ITR Sequences Sequence TAU_ITR138 (SEQ ID NO: 2188) Regions Region SEQ ID NO Region length 5′ ITR 2076 130 CAG promoter 2080 1715 CMVie 2081 299 CBA min. 2082 283 Signal 1740 57 VH 1821 351 VL 1939 336 Tag 2118 27 PolyA 2122 127 3′ ITR 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2188 (TAU_ITR138) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, an IPN002 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

TABLE 56 Sequence Regions in ITR to ITR Sequences TAU_ITR152 TAU_ITR153 TAU_ITR154 TAU_ITRI55 TAU_ITR150 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2202) 2203) 2204) 2205) 2200) Region Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 2076 130 CAG 2238 1714 2238 1714 2238 1714 2238 1714 2080 1715 promoter CMVie 2081 299 2081 299 2081 299 2081 299 2081 299 CBA min. 2082 283 2082 283 2082 283 2082 283 2082 283 Signal 1861 57 1861 57 1861 57 1861 57 1861 57 VL 1939 336 1939 336 1939 336 1939 336 1939 336 Linker 2247 45 2248 60 2250 75 2259 90 2245 15 VH 1821 351 1821 351 1821 351 1821 351 1821 351 Tag 2118 27 2118 27 2118 27 2118 27 2118 27 PolyA 2122 127 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2202 (TAU_ITR152) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal sequence, an IPN002 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), an IPN002 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2203 (TAU_ITR153) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal sequence, an IPN002 antibody light chain variable region, a (G4S)4 linker (“(G4S)4” disclosed as SEQ ID NO: 4540), an IPN002 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2204 (TAU_ITR154) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal sequence, an IPN002 antibody light chain variable region, a (G4S)5 linker (“(G4S)5” disclosed as SEQ ID NO: 4538), an IPN002 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2205 (TAU_ITR155) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal sequence, an IPN002 antibody light chain variable region, a (G4S)6 linker (“(G4S)4” disclosed as SEQ ID NO: 4541), an IPN002 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2200 (TAU_ITR150) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal sequence, an IPN002 antibody light chain variable region, a G4S linker (“G4S” disclosed as SEQ ID NO: 4535), an IPN002 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

TABLE 57 Sequence Regions in ITR to ITR Sequences TAU_ITR200 TAU_ITR201 TAU_ITR202 TAU_ITR203 TAU_ITR211 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2272) 2273) 2274) 2275) 2283) Region Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 2076 130 Promoter 2085 699 2085 699 2085 699 2085 699 2086 557 Intron 2240 566 2240 566 2240 566 2240 566 2240 566 Signal 1740 57 1740 57 1740 57 1740 57 1740 57 VH 1821 351 1821 351 1821 351 1821 351 1821 351 Linker 2245 15 1730 45 2249 75 2252 120 1730 45 VL 1939 336 1939 336 1939 336 1939 336 1939 336 Tag 2118 27 2118 27 2118 27 2118 27 2118 27 PolyA 2122 127 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2272 (TAU_ITR200) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a G4S linker (“G4S” disclosed as SEQ ID NO: 4535), an IPN002 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2273 (TAU_ITR201) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), an IPN002 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2274 (TAU_ITR202) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a (G4S)5 linker (“(G4S)5” disclosed as SEQ ID NO: 4538), an IPN002 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2275 (TAU_ITR203) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a (G4S)8 linker (“(G4S)8” disclosed as SEQ ID NO: 4542), an IPN002 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2283 (TAU_ITR211) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a hSYN promoter, a human beta-globin intron region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), an IPN002 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

TABLE 58 Sequence Regions in ITR to ITR Sequences TAU_ITR206 TAU_ITR215 TAU_ITR216 TAU_ITR214 TAU_ITR144 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2278) 2287) 2288) 2286) 2194) Region Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 2076 130 Promoter 2085 699 2086 557 2086 557 2086 557 2239 380 Intron 2240 566 2240 566 2240 566 2240 566 2240 566 Signal 1861 57 1861 57 1861 57 1861 57 1861 57 VL 1939 336 1939 336 1939 336 1939 336 1939 336 Linker 2250 75 2247 45 2250 75 2245 15 2245 15 VH 1821 351 1821 351 1821 351 1821 351 1821 351 Tag 2118 27 2118 27 2118 27 2118 27 2118 27 PolyA 2122 127 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2278 (TAU_ITR206) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a light chain signal sequence, an IPN002 antibody light chain variable region, a (G4S)5 linker (“(G4S)5” disclosed as SEQ ID NO: 4538), an IPN002 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2287 (TAU_ITR215) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a hSYN promoter, a human beta-globin intron region, a light chain signal sequence, an IPN002 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), an IPN002 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2288 (TAU_ITR216) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a hSYN promoter, a human beta-globin intron region, a light chain signal sequence, an IPN002 antibody light chain variable region, a (G4S)5 linker (“(G4S)5” disclosed as SEQ ID NO: 4538), an IPN002 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2286 (TAU_ITR214) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a hSYN promoter, a human beta-globin intron region, a light chain signal sequence, an IPN002 antibody light chain variable region, a G4S linker (“G4S” disclosed as SEQ ID NO: 4535), an IPN002 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2194 (TAU_ITR144) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a human beta-globin intron region, a light chain signal sequence, an IPN002 antibody light chain variable region, a G4S linker (“G4S” disclosed as SEQ ID NO: 4535), an IPN002 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

TABLE 59 Sequence Regions in ITR to ITR Sequences TAU_ITR212 TAU_ITR213 TAU_ITR210 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2284) 2285) 2282) Region Region Region Sequence SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 Promoter 2086 557 2086 557 2086 557 Intron 2240 566 2240 566 2240 566 Signal 1740 57 1740 57 1740 57 VH 1821 351 1821 351 1821 351 Linker 2249 75 2252 120 2245 15 VL 1939 336 1939 336 1939 336 Tag 2118 27 2118 27 2118 27 PolyA 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2284 (TAU_ITR212) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a hSYN promoter, a human beta-globin intron region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a (G4S)5 linker (“(G4S)5” disclosed as SEQ ID NO: 4538), an IPN002 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2285 (TAU_ITR213) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a hSYN promoter, a human beta-globin intron region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a (G4S)8 linker (“(G4S)8” disclosed as SEQ ID NO: 4542), an IPN002 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2282 (TAU_ITR210) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a hSYN promoter, a human beta-globin intron region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a G4S linker (G4S″ disclosed as SEQ ID NO: 4535), an IPN002 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

TABLE 60 Sequence Regions in ITR to ITR Sequences TAU_ITR131 TAU_ITR132 TAU_ITR133 TAU_ITR134 TAU_ITR135 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2181) 2182) 2183) 2184) 2185) Region Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 2076 130 Promoter 2239 380 2239 380 2239 380 2239 380 2239 380 Intron 2240 566 2240 566 2240 566 2240 566 2240 566 Signal 1740 57 1740 57 1740 57 1740 57 1740 57 VH 1821 351 1821 351 1821 351 1821 351 1821 351 Constant 1864 321 1864 321 1864 321 1864 321 1864 321 Linker 2245 15 2246 30 1730 45 2254 60 2249 75 VL 1939 336 1939 336 1939 336 1939 336 1939 336 Tag 2118 27 2118 27 2118 27 2118 27 2118 27 PolyA 2122 127 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2181 (TAU_ITR131) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a human beta-globin intron region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a light chain constant region, a G4S linker (“G4S” disclosed as SEQ ID NO: 4535), an IPN002 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2182 (TAU_ITR132) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a human beta-globin intron region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a light chain constant region, a (G4S)2 linker (“(G4S)4” disclosed as SEQ ID NO: 4539), an IPN002 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2183 (TAU_ITR133) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a human beta-globin intron region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a light chain constant region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), an IPN002 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2184 (TAU_ITR134) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a human beta-globin intron region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a light chain constant region, a (G4S)4 linker (“(G4S)4” disclosed as SEQ ID NO: 4540), an IPN002 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2185 (TAU_ITR135) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a human beta-globin intron region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a light chain constant region, a (G4S)5 linker (“(G4S)5” disclosed as SEQ ID NO: 4538), an IPN002 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

TABLE 61 Sequence Regions in ITR to ITR Sequences Sequence TAU_ITR136 (SEQ ID NO: 2186) Regions Region SEQ ID NO Region length 5′ ITR 2076 130 Promoter 2239 380 Intron 2240 566 Signal 1740 57 VH 1821 351 Constant 1864 321 Linker 2251 90 VL 1939 336 Tag 2118 27 PolyA 2122 127 3′ ITR 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2186 (TAU_ITR136) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a human beta-globin intron region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a light chain constant region, a (G4S)6 linker (“(G4S)4” disclosed as SEQ ID NO: 4541), an IPN002 antibody light chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

TABLE 62 Sequence Regions in ITR to ITR Sequences Sequence TAU_ITR121 (SEQ ID NO: 2171) Regions Region SEQ ID NO Region length 5′ ITR 2076 130 Promoter 2239 380 Intron 2240 566 Signal 2241 57 VH 1821 351 Constant 2242 309 Linker 1724 12 Linker 1726 54 Constant 1864 321 PolyA 2122 127 3′ ITR 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2171 (TAU_ITR121) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a human beta-globin intron region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

TABLE 63 Sequence Regions in ITR to ITR Sequences TAU_ITR123 TAU_ITR124 (SEQ ID NO: 2173) (SEQ ID NO: 2174) Sequence Region SEQ Region Region SEQ Region Regions ID NO length ID NO length 5′ ITR 2076 130 2076 130 Promoter 2239 380 2239 380 Intron 2240 566 2240 566 Signal 2241 57 2241 57 VH 1821 351 1821 351 Constant 2243 291 2242 309 Linker 1724 12 1724 12 Linker 1726 54 1726 54 Signal 1861 57 1861 57 VL 1939 336 1939 336 Constant 1864 321 1864 321 PolyA 2122 127 2122 127 3′ ITR 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2173 (TAU_ITR123) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a human beta-globin intron region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, a light chain signal sequence, an IPN002 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2174 (TAU_ITR124) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a human beta-globin intron region, a heavy chain signal sequence, an IPN002 antibody heavy chain variable region, a heavy chain constant region, a furin cleavage site, a T2A linker, a light chain signal sequence, an IPN002 antibody light chain variable region, a light chain constant region, and a rabbit globin polyadenylation signal sequence.

TABLE 64 Sequence Regions in ITR to ITR Sequences TAU_ITR145 TAU_ITR146 TAU_ITR147 TAU_ITR148 TAU_ITR149 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2195) 2196) 2197) 2198) 2199) Region Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 2076 130 Promoter 2239 380 2239 380 2239 380 2239 380 2239 380 Intron 2240 566 2240 566 2240 566 2240 566 2240 566 Signal 1861 57 1861 57 1861 57 1861 57 1861 57 VL 1939 336 1939 336 1939 336 1939 336 1939 336 Linker 2246 30 1730 45 2254 60 2249 75 2251 90 VH 1821 351 1821 351 1821 351 1821 351 1821 351 Tag 2118 27 2118 27 2118 27 2118 27 2118 27 PolyA 2122 127 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2195 (TAU_ITR145) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a human beta-globin intron region, a light chain signal sequence, an IPN002 antibody light chain variable region, a (G4S)2 linker (“(G4S)4” disclosed as SEQ ID NO: 4539), an IPN002 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2196 (TAU_ITR146) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a human beta-globin intron region, a light chain signal sequence, an IPN002 antibody light chain variable region, a (G4S)3 linker (“(G4S)3” disclosed as SEQ ID NO: 4537), an IPN002 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2197 (TAU_ITR147) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a human beta-globin intron region, a light chain signal sequence, an IPN002 antibody light chain variable region, a (G4S)4 linker (“(G4S)4” disclosed as SEQ ID NO: 4540), an IPN002 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2198 (TAU_ITR148) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a human beta-globin intron region, a light chain signal sequence, an IPN002 antibody light chain variable region, a (G4S)5 linker (“(G4S)5” disclosed as SEQ ID NO: 4538), an IPN002 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2199 (TAU_ITR149) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region, a human beta-globin intron region, a light chain signal sequence, an IPN002 antibody light chain variable region, a (G4S)6 linker (“(G4S)4” disclosed as SEQ ID NO: 4541), an IPN002 antibody heavy chain variable region, an HA tag, and a rabbit globin polyadenylation signal sequence.

TABLE 65 Sequence Regions in ITR to ITR Sequences Sequence TAU_ITR244 (SEQ ID NO: 2316) Regions Region SEQ ID NO Region length 5′ ITR 2076 130 CAG promoter 2080 1715 CMVie 2081 299 CBA min. 2082 283 VH 1838 1377 Linker 1724 12 Linker 1726 54 VL 1936 720 PolyA 2122 127 3′ ITR 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2316 (TAU_ITR244) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a PHF1 antibody heavy chain variable region, a furin cleavage site, a T2A linker, a PHF1 antibody light chain variable region and a rabbit beta globin polyadenylation signal sequence.

TABLE 66 Sequence Regions in ITR to ITR Sequences Sequence TAU_ITR248 (SEQ ID NO: 2320) Regions Region SEQ ID NO Region length 5′ ITR 2077 141 CAG promoter 2080 1715 CMVie 2081 299 CBA min. 2082 283 VH 2169 435 Linker 1730 45 VL 1957 339 PolyA 2123 477 Filler 2126 1240 3′ ITR 2079 141

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2320 (TAU_ITR248) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a PHF1 antibody heavy chain variable region, a furin cleavage site, a PHF1 antibody light chain variable region, a rabbit beta globin polyadenylation signal sequence and a human albumin derived filler sequence.

TABLE 67 Sequence Regions in ITR to ITR Sequences TAU_ITR243 TAU_ITR242 TAU_ITR241 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2315) 2314) 2313) Region Region Region Sequence SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 Promoter 2084 654 2085 699 5086 557 Intron 2240 566 2240 566 2240 566 VH 1838 1377 1838 1377 1838 1377 Linker 1724 12 1724 12 1724 12 Linker 1726 54 1726 54 1726 54 VL 1936 720 1936 720 1936 720 PolyA 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2315 (TAU_ITR243) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, a human beta-globin intron region, a PHF1 antibody heavy chain variable region, a furin cleavage site, a T2A linker, an PHF1 antibody light chain variable region, and a rabbit globin polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2314 (TAU_ITR242) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a PHF1 antibody heavy chain variable region, a furin cleavage site, a T2A linker, an PHF1 antibody light chain variable region, and a rabbit globin polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2313 (TAU_ITR241) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a synapsin promoter, a human beta-globin intron region, a PHF1 antibody heavy chain variable region, a furin cleavage site, a T2A linker, an PHF1 antibody light chain variable region, and a rabbit globin polyadenylation sequence.

TABLE 68 Sequence Regions in ITR to ITR Sequences TAU_ITR245 TAU_ITR246 TAU_ITR247 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2317) 2318) 2319) Region Region Region Sequence SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length 5′ ITR 2077 141 2077 141 2077 141 CBA 2084 654 2084 654 2084 654 Promoter Intron 2256 491 2257 387 2258 292 VH 2170 408 2170 408 2170 408 Linker 1730 45 1730 45 1730 45 VL 1957 339 1957 339 1957 339 HA Tag 2118 27 2118 27 2118 27 PolyA 2122 127 2122 127 2122 127 3′ ITR 2079 141 2079 141 2079 141

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2317 (TAU_ITR245) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, a human beta-globin intron region, a PHF1 antibody heavy chain variable region, a furin cleavage site, an PHF1 antibody light chain variable region, a HA tag and a rabbit globin polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2318 (TAU_ITR246) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, a human beta-globin intron region, a PHF1 antibody heavy chain variable region, a furin cleavage site, an PHF1 antibody light chain variable region, a HA tag and a rabbit globin polyadenylation sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2319 (TAU_ITR247) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, a human beta-globin intron region, a PHF1 antibody heavy chain variable region, a furin cleavage site, an PHF1 antibody light chain variable region, a HA tag and a rabbit globin polyadenylation sequence.

TABLE 69 Sequence Regions in ITR to ITR Sequences Sequence TAU_ITR249 (SEQ ID NO: 2321) Regions Region SEQ ID NO Region length 5′ ITR 2077 141 CBA promoter 2084 654 VH 2169 435 Linker 1730 45 VL 1957 339 PolyA 2123 477 Filler 2126 1240 3′ ITR 2079 141

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2321 (TAU_ITR249) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CBA promoter, a PHF1 antibody heavy chain variable region, a furin cleavage site, a PHF1 antibody light chain variable region, a rabbit beta globin polyadenylation signal sequence and a human albumin derived filler sequence.

TABLE 70 Sequence Regions in ITR to ITR Sequences TAU_ITR158 TAU_ITR170 TAU_ITR171 TAU_ITR172 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2208) 2220) 2221) 2222) Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 CAG 2080 1715 2080 1715 2080 1715 2080 1715 promoter CMVie 2081 299 2081 299 2081 299 2081 299 CBA min. 2082 283 2082 283 2082 283 2082 283 Signal 1740 57 1740 57 1740 57 1740 57 VH 1859 354 2241 348 2241 348 1859 354 Linker 2247 45 2247 45 2247 45 2247 45 VL 1980 321 1980 321 1980 321 1980 321 HA Tag 2118 27 2118 27 2118 27 2118 27 PolyA 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2208 (TAU_ITR158) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal, a PT3 antibody heavy chain variable region, a (G4S)3 linker, a light chain signal, a PT3 antibody light chain variable region, a HA tag, and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2220 (TAU_ITR170) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal, a PT3 antibody heavy chain variable region, a (G4S)3 linker, a light chain signal, a PT3 antibody light chain variable region, a HA tag, and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2221 (TAU_ITR171) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal, a PT3 antibody heavy chain variable region, a (G4S)3 linker, a light chain signal, a PT3 antibody light chain variable region, a HA tag, and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2222 (TAU_ITR172) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal, a PT3 antibody heavy chain variable region, a (G4S)3 linker, a light chain signal, a PT3 antibody light chain variable region, a HA tag, and a rabbit beta globin polyadenylation signal sequence

TABLE 71 Sequence Regions in ITR to ITR Sequences TAU_ITR173 TAU_ITR174 TAU_ITR175 TAU_ITR179 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2223) 2224) 2225) 2229) Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 CAG 2080 1715 2080 1715 2080 1715 2080 1715 promoter CMVie 2081 299 2081 299 2081 299 2081 299 CBA min. 2082 283 2082 283 2082 283 2082 283 Signal 1740 57 1740 57 1740 57 1740 57 VH 1859 354 1859 354 1859 354 1859 354 Linker 2247 45 2247 45 2247 45 2247 45 VL 1980 321 1980 321 1980 321 1980 321 HA Tag 2118 27 2118 27 2118 27 2118 27 PolyA 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2223 (TAU_ITR173) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal, a PT3 antibody heavy chain variable region, a (G4S)3 linker, a light chain signal, a PT3 antibody light chain variable region, a HA tag, and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2224 (TAU_ITR174) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal, a PT3 antibody heavy chain variable region, a (G4S)3 linker, a light chain signal, a PT3 antibody light chain variable region, a HA tag, and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2225 (TAU_ITR175) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal, a PT3 antibody heavy chain variable region, a (G4S)3 linker, a light chain signal, a PT3 antibody light chain variable region, a HA tag, and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2229 (TAU_ITR179) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal, a PT3 antibody heavy chain variable region, a (G4S)3 linker, a light chain signal, a PT3 antibody light chain variable region, a HA tag, and a rabbit beta globin polyadenylation signal sequence.

TABLE 72 Sequence Regions in ITR to ITR Sequences TAU_ITR157 TAU_ITR159 (SEQ ID NO: 2207) (SEQ ID NO: 2209) Sequence Region SEQ Region Region SEQ Region Regions ID NO length ID NO length 5′ ITR 2076 130 2076 130 CAG promoter 2080 1715 2080 1715 CMVie 2081 299 2081 299 CBA min. 2082 283 2082 283 Signal 1740 57 1740 57 VH 1859 354 1859 354 Linker 2246 30 2248 60 VL 1980 321 1980 321 HA Tag 2118 27 2118 27 PolyA 2122 127 2122 127 3′ ITR 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2207 (TAU_ITR157) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal, a PT3 antibody heavy chain variable region, a (G4S)2 linker, a light chain signal, a PT3 antibody light chain variable region, a HA tag, and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2209 (TAU_ITR159) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal, a PT3 antibody heavy chain variable region, a (G4S)4 linker, a light chain signal, a PT3 antibody light chain variable region, a HA tag, and a rabbit beta globin polyadenylation signal sequence.

TABLE 73 Sequence Regions in ITR to ITR Sequences TAU_ITR104 TAU_ITR181 (SEQ ID NO: 2154) (SEQ ID NO: 2231) Sequence Region SEQ Region Region SEQ Region Regions ID NO length ID NO length 5′ ITR 2076 130 2076 130 CAG promoter 2080 1715 2080 1715 CMVie 2081 299 2081 299 CBA min. 2082 283 2082 283 Signal 1740 57 1740 57 VH 1859 354 1859 354 Constant 1742 969 2243 291 Linker 1725 12 1725 12 Linker 1727 75 1727 75 Signal 1861 57 1861 57 VL 1980 321 1980 321 Constant 1864 321 1864 321 PolyA 2122 127 2122 127 3′ ITR 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2154 (TAU_ITR104) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal, a PT3 antibody heavy chain variable and constant region, a furin cleavage site, a F2A linker, a light chain signal, a PT3 antibody light chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2231 (TAU_ITR181) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal, a PT3 antibody heavy chain variable and constant region, a furin cleavage site, a F2A linker, a light chain signal, a PT3 antibody light chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

TABLE 74 Sequence Regions in ITR to ITR Sequences TAU_ITR112 TAU_ITR120 TAU_ITR180 TAU_ITR182 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2162) 2162) 2230) 2232) Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 CAG 2080 1715 2080 1715 2080 1715 2080 1715 promoter CMVie 2081 299 2081 299 2081 299 2081 299 CBA min. 2082 283 2082 283 2082 283 2082 283 Signal 1740 57 1740 57 1740 57 1740 57 VH 1859 354 1859 354 1859 354 1859 354 Constant 1742 969 1742 969 2243 291 2242 309 Linker 1724 12 1724 12 1724 12 1724 12 Linker 1726 54 1726 54 1726 54 1726 54 Signal 1861 57 1861 57 1861 57 1861 57 VL 1980 321 1980 321 1980 321 1980 321 Constant 1864 321 1864 321 1864 321 1864 321 PolyA 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2162 (TAU_ITR112) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal, a PT3 antibody heavy chain variable and constant region, a furin cleavage site, a T2A linker, a light chain signal, a PT3 antibody light chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2162 (TAU_ITR120) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal, a PT3 antibody heavy chain variable and constant region, a furin cleavage site, a T2A linker, a light chain signal, a PT3 antibody light chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2230 (TAU_ITR180) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal, a PT3 antibody heavy chain variable and constant region, a furin cleavage site, a T2A linker, a light chain signal, a PT3 antibody light chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2232 (TAU_ITR182) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal, a PT3 antibody heavy chain variable and constant region, a furin cleavage site, a T2A linker, a light chain signal, a PT3 antibody light chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

TABLE 75 Sequence Regions in ITR to ITR Sequences TAU_ITR193 TAU_ITR190 (SEQ ID NO: 2265) (SEQ ID NO: 2262) Sequence Region SEQ Region Region SEQ Region Regions ID NO length ID NO length 5′ ITR 2076 130 2076 130 CAG promoter 2080 1715 2080 1715 CMVie 2081 299 2081 299 CBA min. 2082 283 2082 283 Signal 1740 57 1740 57 VH 1859 354 1859 354 Constant 2242 309 2242 309 Hinge 1737 198 1737 198 Linker 1724 12 1724 12 Linker 1727 75 1726 54 Signal 1861 57 1861 57 VL 1980 321 1980 321 Constant 1864 321 1864 321 PolyA 2122 127 2122 127 3′ ITR 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2265 (TAU_ITR193) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal, a PT3 antibody heavy chain variable and constant region, a hinge region, a furin cleavage site, a F2A linker, a light chain signal, a PT3 antibody light chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2262 (TAU_ITR190) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal, a PT3 antibody heavy chain variable and constant region, a hinge region, a furin cleavage site, a T2A linker, a light chain signal, a PT3 antibody light chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

TABLE 76 Sequence Regions in ITR to ITR Sequences Sequence TAU_ITR156 (SEQ ID NO: 2206) Regions Region SEQ ID NO Region length 5′ ITR 2076 130 CAG promoter 2080 1715 CMVie 2081 299 CBA min. 2082 283 Signal 1861 57 VH 1859 354 Linker 2247 45 VL 1980 321 HA Tag 2118 27 PolyA 2122 127 3′ ITR 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2206 (TAU_ITR156) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal, a PT3 antibody heavy chain variable region, a (G4S)3 linker, a PT3 antibody light chain variable region, a HA tag and a rabbit beta globin polyadenylation signal sequence.

TABLE 77 Sequence Regions in ITR to ITR Sequences Sequence TAU_ITR160 (SEQ ID NO: 2210) Regions Region SEQ ID NO Region length 5′ ITR 2076 130 CAG promoter 2080 1715 CMVie 2081 299 CBA min. 2082 283 Signal 1740 57 VL 1980 321 Linker 2247 45 VH 1859 354 HA Tag 2118 27 PolyA 2122 127 3′ ITR 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2210 (TAU_ITR160) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a heavy chain signal, a PT3 antibody light chain variable region, a (G4S)3 linker, a PT3 antibody heavy chain variable region, a HA tag and a rabbit beta globin polyadenylation signal sequence.

TABLE 78 Sequence Regions in ITR to ITR Sequences TAU_ITR161 TAU_ITR162 TAU_ITR196 TAU_ITR163 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2211) 2212) 2268) 2213) Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 2076 130 CAG 2080 1715 2080 1715 2080 1715 2080 1715 promoter CMVie 2081 299 2081 299 2081 299 2081 299 CBA min. 2082 283 2082 283 2082 283 2082 283 Signal 1861 57 1861 57 1861 57 1861 57 VL 1980 321 1980 321 1980 321 1980 321 Linker 2246 30 2247 45 2247 45 2248 60 VH 1859 354 1859 354 1859 354 1859 354 HA Tag 2118 27 2118 27 2255 18 2118 27 PolyA 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2211 (TAU_ITR161) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal, a PT3 antibody light chain variable region, a (G4S)2 linker, a PT3 antibody heavy chain variable region, a HA tag and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2212 (TAU_ITR162) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal, a PT3 antibody light chain variable region, a (G4S)3 linker, a PT3 antibody heavy chain variable region, a HA tag and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2268 (TAU_ITR196) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal, a PT3 antibody light chain variable region, a (G4S)3 linker, a PT3 antibody heavy chain variable region, a HA tag and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2213 (TAU_ITR163) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal, a PT3 antibody light chain variable region, a (G4S)4 linker, a PT3 antibody heavy chain variable region, a HA tag and a rabbit beta globin polyadenylation signal sequence.

TABLE 79 Sequence Regions in ITR to ITR Sequences TAU_ITR108 TAU_ITR184 TAU_ITR116 TAU_ITR183 TAU_ITR185 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2158) 2234) 2166) 2233) 2235) Region Region Region Region Region Sequence SEQ Region SEQ Region SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length ID NO length ID NO length 5′ ITR 2076 130 2676 130 2076 130 2076 130 2076 130 CAG 2080 1715 2080 1715 2080 1715 2080 1715 2080 1715 promoter CMVie 2081 299 2081 299 2081 299 2081 299 2081 299 CBA min. 2082 283 2082 283 2082 283 2082 283 2082 283 Signal 1861 57 1861 57 1861 57 1861 57 1861 57 VL 1980 321 1980 321 1980 321 1980 321 1980 321 Constant 1864 321 1864 321 1864 321 1864 321 1864 321 Linker 1727 75 1727 75 1726 54 1726 54 1726 54 Signal 1740 57 1740 57 2241 57 1740 57 1740 57 VH 1859 354 1859 354 1859 354 1859 354 1859 354 Constant 1742 969 2243 291 1742 969 2243 291 2242 309 Poly A 2122 127 2122 127 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2158 (TAU_ITR108) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal, a PT3 antibody light chain variable and constant region, a F2A linker, a heavy chain signal, a PT3 antibody heavy chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2234 (TAU_ITR184) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal, a PT3 antibody light chain variable and constant region, a F2A linker, a heavy chain signal, a PT3 antibody heavy chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2166 (TAU_ITR116) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal, a PT3 antibody light chain variable and constant region, a T2A linker, a heavy chain signal, a PT3 antibody heavy chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2233 (TAU_ITR183) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal, a PT3 antibody light chain variable and constant region, a T2A linker, a heavy chain signal, a PT3 antibody heavy chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2235 (TAU_ITR185) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal, a PT3 antibody light chain variable and constant region, a T2A linker, a heavy chain signal, a PT3 antibody heavy chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

TABLE 80 Sequence Regions in ITR to ITR Sequences TAU_ITR186 TAU_ITR187 (SEQ ID NO: 2236) (SEQ ID NO: 2237) Sequence Region SEQ Region Region SEQ Region Regions ID NO length ID NO length 5′ ITR 2076 130 2076 130 CAG promoter 2080 1715 2080 1715 CMVie 2081 299 2081 299 CBA min. 2082 283 2082 283 Signal 1861 57 1861 57 VL 1980 321 1980 321 Constant 1864 321 1864 321 Linker 1724 12 1724 12 Linker 1726 54 1726 54 Signal 1740 57 1740 57 VH 1859 354 1859 354 Constant 2243 291 2242 309 PolyA 2122 127 2122 127 3′ ITR 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2236 (TAU_ITR186) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal, a PT3 antibody light chain variable and constant region, a furin cleavage site, a T2A linker, a heavy chain signal, a PT3 antibody heavy chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2237 (TAU_ITR187) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a light chain signal, a PT3 antibody light chain variable and constant region, a furin cleavage site, a T2A linker, a heavy chain signal, a PT3 antibody heavy chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

TABLE 81 Sequence Regions in ITR to ITR Sequences TAU_ITR176 TAU_ITR177 TAU_ITR178 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2226) 2227) 2228) Region Region Region Sequence SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 CAG 2080 1715 2080 1715 2080 1715 promoter CMVie 2081 299 2081 299 2081 299 CBA mm. 2082 283 2082 283 2082 283 VH 1859 354 1859 354 1859 354 Linker 2247 45 2247 45 2247 45 VL 1980 321 1980 321 1980 321 HA Tag 2118 37 2118 27 2118 27 Poly A 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2226 (TAU_ITR176) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a PT3 antibody heavy chain variable region, a (G4S)3 linker, a PT3 antibody light chain variable region a HA tag and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2227 (TAU_ITR177) which comprises a 5 inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a PT3 antibody heavy chain variable region, a (G4S)3 linker, a PT3 antibody light chain variable region, a HA tag and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2228 (TAU_ITR178) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CAG promoter comprising a CMVie region and a minimal CBA promoter region, a PT3 antibody heavy chain variable region, a (G4S)3 linker, a PT3 antibody light chain variable region, a HA tag and a rabbit beta globin polyadenylation signal sequence.

TABLE 82 Sequence Regions in ITR to ITR Sequences TAU_ITR105 TAU_ITR113 TAU_ITR189 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2155) 2163) 2261) Region Region Region Sequence SEQ Region SEQ ID Region SEQ ID Region Regions ID NO length NO length NO length 5′ ITR 2076 130 2076 130 2076 130 GFAP 2085 699 2085 699 2085 699 Promoter Intron 2240 566 2240 566 2240 566 Signal 1740 57 1740 57 1740 57 VH 1859 354 1859 354 1859 354 Constant 1742 969 1742 969 2243 291 Linker 1725 12 1724 12 1724 12 Linker 1727 75 1726 54 1726 54 Signal 1980 321 1980 321 1980 321 VL 1864 321 1864 321 1864 321 Poly A 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2155 (TAU_ITR105) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a heavy chain signal, a PT3 antibody heavy chain variable and constant region, a furin cleavage site, a F2A linker, a light chain signal, a PT3 antibody light chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2163 (TAU_ITR113) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a heavy chain signal, a PT3 antibody heavy chain variable and constant region, a furin cleavage site, a T2A linker, a light chain signal, a PT3 antibody light chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2261 (TAU_ITR189) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a heavy chain signal, a PT3 antibody heavy chain variable and constant region, a furin cleavage site, a T2A linker, a light chain signal, a PT3 antibody light chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

TABLE 83 Sequence Regions in ITR to ITR Sequences TAU_ITR195 TAU_ITR192 (SEQ ID NO: 2267) (SEQ ID NO: 2264) Sequence Region SEQ Region Region SEQ Region Regions ID NO length ID NO length 5′ ITR 2076 130 2076 130 GFAP Promoter 2085 699 2085 699 Intron 2240 566 2240 566 Signal 1740 57 1740 57 VH 1859 354 1859 354 Constant 2242 309 2242 309 Hinge 1737 198 1737 198 Linker 1725 12 1724 12 Linker 1727 75 1726 54 Signal 1861 57 1861 57 VL 1864 321 1864 321 PolyA 2122 127 2122 127 3′ ITR 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2267 (TAU_ITR195) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a heavy chain signal, a PT3 antibody heavy chain variable and constant region, a hinge region, a furin cleavage site, a F2A linker, a light chain signal, a PT3 antibody light chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2264 (TAU_ITR192) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a heavy chain signal, a PT3 antibody heavy chain variable and constant region, a hinge region, a furin cleavage site, a T2A linker, a light chain signal, a PT3 antibody light chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

TABLE 84 Sequence Regions in ITR to ITR Sequences TAU_ITR164 TAU_ITR165 TAU_ITR166 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2214) 2215) 2216) Region Region Region Sequence SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 GFAP 2085 699 2085 699 2085 699 Promoter Intron 2240 566 2240 566 2240 566 Signal 1861 57 1861 57 1861 57 VL 1980 321 1980 321 1980 321 Linker 2246 30 2247 45 2248 60 VH 1859 354 1859 354 1859 354 HA Tag 2118 27 2118 27 2118 27 Poly A 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2214 (TAU_ITR164) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a light chain signal, a PT3 antibody light chain variable region, a (G4S)2 linker, a PT3 antibody heavy chain variable region, a HA tag and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2215 (TAU_ITR165) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a light chain signal, a PT3 antibody light chain variable region, a (G4S)3 linker, a PT3 antibody heavy chain variable region, a HA tag and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2216 (TAU_ITR166) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region a GFAP promoter, a human beta-globin intron region, a light c a 9 signal, a PT3 antibody light chain variable region, a (G4S)4 linker, a PT3 antibody heavy chain variable region, a HA tag and a rabbit beta globin polyadenylation signal sequence.

TABLE 85 Sequence Regions in ITR to ITR Sequences TAU_ITR109 TAU_ITR117 (SEQ ID NO: 2159) (SEQ ID NO: 2167) Sequence Region SEQ Region Region SEQ Region Regions ID NO length ID NO length 5′ ITR 2076 130 2076 130 GFAP Promoter 2085 699 2085 699 Intron 2240 566 2240 566 Signal 1861 57 1861 57 VL 1980 321 1980 321 Constant 1864 321 1864 321 Linker 1727 75 1826 54 Signal 1740 57 2241 57 VH 1859 354 1859 354 Constant 1742 969 1742 969 PolyA 2122 127 2122 127 3′ ITR 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2159 (TAU_ITR9) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a light chain signal, a 3 antibody light chain variable and constant region, a F2A linker, a heavy chain signal, a PT3 antibody heavy chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2167 (TAU_ITR117) which comprises a 5 inverted terminal repeat (FR) sequence region and a 3′ ITR sequence region, a GFAP promoter, a human beta-globin intron region, a light chain signal, a PT3 antibody light chain variable and constant region, a T2A linker, a heavy chain signal, a PT3 antibody heavy chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

TABLE 86 Sequence Regions in ITR to ITR Sequences TAU_ITR106 TAU_ITR114 TAU_ITR188 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2156) 2164) 2260) Region Region Region Sequence SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 SYN 2086 557 2086 557 2086 557 Promoter Intron 2240 566 2240 566 2240 566 Signal 1740 57 1740 57 1740 57 VH 1859 354 1859 354 1859 354 Constant 1742 969 1742 969 2243 291 Linker 1725 12 1724 12 1724 12 Linker 1727 75 1726 54 1726 54 Signal 1861 57 1861 57 1861 57 VL 1980 321 1980 231 1980 231 Constant 1864 321 1864 321 1864 321 Poly A 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2156 (TAU_ITR106) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a synapsin promoter, a human beta-globin intron region, a heavy chain signal, a PT3 antibody heavy chain variable and constant region, a furin cleavage site, a F2A linker, a light chain signal, a PT3 antibody light chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2164 (TAU_ITR114) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a synapsin promoter, a human beta-globin intron region, a heavy chain signal, a PT3 antibody heavy chain variable and constant region, a furin cleavage site, a F2A linker, a light chain signal, a PT3 antibody light chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2260 (TAU_ITR188) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a synapsin promoter, a human beta-globin intron region, a heavy chain signal, a PT3 antibody heavy chain variable and constant region, a furin cleavage site, a F2A linker, a light chain signal, a PT3 antibody light chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

TABLE 87 Sequence Regions in ITR to ITR Sequences TAU_ITR194 TAU_ITR191 (SEQ ID NO: 2266) (SEQ ID NO: 2263) Sequence Region SEQ Region Region SEQ Region Regions ID NO length ID NO length 5′ ITR 2076 130 2076 130 SYN Promoter 2086 557 2086 557 Intron 2240 566 2240 566 Signal 1740 57 1740 57 VH 1859 354 1859 354 Constant 2242 309 2242 309 Hinge 1737 198 1737 198 Linker 1724 12 1724 12 Linker 1727 75 1726 54 Signal 1861 54 1861 57 VL 1980 321 1980 321 Constant 1864 321 1864 321 PolyA 2122 127 2122 127 3′ ITR 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2266 (TAU_ITR194) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a synapsin promoter, a human beta-globin intron region, a heavy chain signal, a PT3 antibody heavy chain variable and constant region, a hinge region, a furin cleavage site, a F2A linker, a light chain signal, a PT3 antibody light chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2263 (TAU_ITR191) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a synapsin promoter, a human beta-globin intron region, a heavy chain signal, a PT3 antibody heavy chain variable and constant region, a hinge region, a furin cleavage site, a T2A linker, a light chain signal, a PT3 antibody light chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

TABLE 88 Sequence Regions in ITR to ITR Sequences TAU_ITR167 TAU_ITR168 TAU_ITR169 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2217) 2218) 2219) Region Region Region Sequence SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 SYN 2086 557 2086 557 2086 557 Promoter Intron 2240 566 2240 566 2240 566 Signal 1861 57 1861 57 1861 57 VL 1980 321 1980 321 1980 321 Linker 2246 30 2247 45 2248 60 VH 1859 354 1859 354 1859 354 HA Tag 2118 27 2118 27 2118 27 Poly A 2122 127 212.2 127 2122 127 3′ ITR 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2217 (TAU_ITR167) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a synapsin promoter, a human beta-globin intron region, a light chain signal, a PT3 antibody light chain variable region, a (G4S)2 linker, a PT3 antibody heavy chain variable region, a HA tag and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2218 (TAU_ITR168) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a synapsin promoter, a human beta-globin intron region, a light chain signal, a PT3 antibody light chain variable region, a (G4S)3 linker, a PT3 antibody heavy chain variable region, a HA tag and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, tbc AAV particle genome comprises SEQ ID NO: 2219 (TAU_ITR169) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a synapsin promoter, a human beta-globin intron region, a light chain signal, a PT3 antibody light chain variable region, a (G4S)4 linker, a PT3 antibody heavy chain variable region, a HA tag and a rabbit beta globin polyadenylation signal sequence.

TABLE 89 Sequence Regions in ITR to ITR Sequences TAU_ITR110 TAU_ITR118 (SEQ ID NO: 2160) (SEQ ID NO: 2168) Sequence Region SEQ Region Region SEQ Region Regions ID NO length ID NO length 5′ ITR 2076 130 2076 130 SYN Promoter 2086 557 2086 557 Intron 2240 566 2240 566 Signal 1861 57 1861 57 VL 1980 321 1980 321 Constant 1864 321 1864 321 Linker 1727 75 1726 54 Signal 1740 57 2241 57 VH 1859 354 1859 354 Constant 1742 969 1742 969 PolyA 2122 127 2122 127 3′ ITR 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2160 (TAU_ITR110) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a synapsin promoter, a human beta-globin intron region, a light chain signal, a PT3 antibody light chain variable region, a F2A linker, a heavy chain signal, a PT3 antibody heavy chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2168 (TAU_ITR18) which comprises a inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a synapsin promoter, a human beta-globin intron region, a light chain signal, a PT3 antibody light chain variable region, a T2A linker, a heavy chain signal, a PT3 antibody heavy chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

TABLE 90 Sequence Regions in ITR to ITR Sequences TAU_ITR103 TAU_ITR111 TAU_ITR119 (SEQ ID NO: (SEQ ID NO: (SEQ ID NO: 2153) 2161) 2161) Region Region Region Sequence SEQ Region SEQ Region SEQ Region Regions ID NO length ID NO length ID NO length 5′ ITR 2076 130 2076 130 2076 130 CMVie 2239 380 2239 380 2239 380 CB 2083 260 2083 260 2083 260 Promoter Intron 2240 566 2240 566 2240 566 Signal 1740 57 1740 57 1740 57 VH 1859 354 1859 354 1859 354 Constant 1742 969 1742 969 1742 969 Linker 1725 12 1724 12 1724 12 Linker 1727 75 1726 54 1726 54 Signal 1861 57 1861 57 1861 57 VL 1980 321 1980 321 1980 321 Constant 1864 321 1864 321 1864 321 Poly A 2122 127 2122 127 2122 127 3′ ITR 2078 130 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2153 (TAU_ITR103) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region a CMVie region and a CB promoter, a human beta-globin intron region, a heavy chain signal, a PT3 antibody heavy chain variable and constant region, a furin cleavage site, a F2A linker, a light chain signal, a PT3 antibody light chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2161 (TAU_ITR11) which comprises a 5 inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region and a CB promoter, a human beta-globin intron region, a heavy chain signal, a PT3 antibody heavy chain variable and constant region, a furin cleavage site, a T2A linker, a light chain signal, a PT3 antibody light chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2161 (TAU_ITR119) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region and a CB promoter, a human beta-globin intron region, a heavy chain signal, a PT3 antibody heavy chain variable and constant region, a furin cleavage site, a T2A linker, a light chain signal, a PT3 antibody light chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

TABLE 91 Sequence Regions in ITR to ITR Sequences TAU_ITR107 TAU_ITR115 (SEQ ID NO: 2157) (SEQ ID NO: 2165) Sequence Region SEQ Region Region SEQ Region Regions ID NO length ID NO length 5′ ITR 2076 130 2076 130 CMVie 2239 380 2239 380 CB Promoter 2083 260 2083 260 Intron 2240 566 2240 566 Signal 1861 57 1861 57 VL 1980 321 1980 321 Constant 1864 321 1864 321 Linker 1727 75 1726 54 Signal 1740 57 2241 57 VH 1859 354 1859 354 Constant 1742 969 1742 969 PolyA 2122 127 2122 127 3′ ITR 2078 130 2078 130

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2157 (TAU_ITR107) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region and a CB promoter, a human beta-globin intron region, a light chain signal, a PT3 antibody light chain variable and constant region, a F2A linker, a heavy chain signal, a PT3 antibody heavy chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the AAV particle genome comprises SEQ ID NO: 2165 (TAU_ITR115) which comprises a 5′ inverted terminal repeat (ITR) sequence region and a 3′ ITR sequence region, a CMVie region and a CB promoter, a human beta-globin intron region, a light chain signal, a PT3 antibody light chain variable and constant region, a F2A linker, a heavy chain signal, a PT3 antibody heavy chain variable and constant region and a rabbit beta globin polyadenylation signal sequence.

In some embodiments, the viral genome may comprise any combination of the following components, including, but not limited to, a 5′ ITR, a promoter region (may comprise one or more component pieces), an intronic region, a Kozak sequence, one or more signal sequences (antibody signal sequences or signal sequence derived from another protein), one or more furin cleavage sites, one or more linker sequences, one or more antibody light chain variable regions, one or more antibody light chain constant regions, one or more antibody heavy chain variable regions, one or more antibody heavy chain constant regions, a polyadenylation sequence, a stuffer sequence, and/or a filler sequence.

In some embodiments, the AAV viral genome comprises, when read in the 5′ to 3′ direction, a 5′ ITR, a promoter region, an optional intronic region, a signal sequence, an antibody light chain region, a linker region, a signal sequence, an antibody heavy chain region, a polyadenylation sequence, an optional filler sequence, and a 3′ ITR.

The viral genome may encode an antibody fragment, such as, but not limited to Fab, F(ab′)2 or scFv fragments. In some embodiments, the viral genome encodes a Fab antibody fragment. In another embodiment, the viral genome encodes an F(ab′)2 antibody fragment. In some embodiments, the viral genome encodes an scFv.

In some embodiments, the viral genome comprising the ITR to ITR sequence, or a fragment thereof, described in Tables 4-6 and 15-91 is packaged in a capsid having a serotype selected from Table 1 to generate an AAV particle. For example, the capsid serotype is VOY101, VOY201, AAVPHP.B, AAVPHP.N, AAV1, AAV2, AAV2 variant, AAV3, AAV2/3 variant, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV9.47, AAV9(hu14), AAV9K449R, AAV10, AAV11, AAV12, AAVrh8, AAVrh10, AAVDJ, or AAVDJ8, or any variant thereof. In some embodiments, the capsid serotype is AAVPHP.B, AAV9, AAV6, AAVrh10, and/or AAVDJ.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1990 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1990 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1990 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1990 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1990 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1990 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1990 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1990 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1990 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1990 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1990 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1990 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1990 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1990 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1990 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1990 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1990 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1990 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1990 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1990 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1990 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1991 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1991 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1991 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1991 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1991 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1991 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1991 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1991 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1991 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1991 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1991 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1991 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1991 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1991 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1991 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1991 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1991 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1991 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1991 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1991 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1991 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1992 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1992 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1992 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1992 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1992 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1992 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1992 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1992 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1992 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1992 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1992 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1992 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1992 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1992 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1992 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1992 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1992 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1992 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1992 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1992 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1992 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1993 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1993 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1993 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1993 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1993 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1993 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1993 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1993 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1993 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1993 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1993 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1993 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1993 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1993 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1993 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1993 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1993 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1993 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1993 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1993 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1993 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1994 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1994 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1994 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1994 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1994 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1994 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1994 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1994 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1994 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1994 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1994 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1994 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1994 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1994 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1994 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1994 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1994 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1994 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1994 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1994 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1994 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1995 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1995 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1995 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1995 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1995 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1995 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1995 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1995 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1995 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1995 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1995 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1995 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1995 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1995 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1995 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1995 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1995 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1995 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1995 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1995 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1995 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1996 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1996 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1996 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1996 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1996 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1996 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1996 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1996 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1996 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1996 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1996 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1996 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1996 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1996 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1996 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1996 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1996 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1996 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1996 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1996 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1996 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1997 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1997 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1997 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1997 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1997 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1997 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1997 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1997 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1997 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1997 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1997 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1997 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1997 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1997 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1997 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1997 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1997 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1997 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1997 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1997 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1997 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1998 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1998 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1998 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1998 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1998 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral gnome comprising SEQ ID NO: 1998 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral gnome comprising SEQ ID NO: 1998 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1998 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1998 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1998 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1998 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1998 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral gnome comprising SEQ ID NO: 1998 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1998 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1998 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1998 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1998 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1998 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1998 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1998 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1998 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1999 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1999 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1999 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1999 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1999 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1999 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1999 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1999 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1999 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1999 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1999 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1999 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1999 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1999 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1999 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1999 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1999 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1999 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1999 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1999 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 1999 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2000 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2000 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2000 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2000 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2000 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2000 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2000 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2000 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2000 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2000 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2000 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2000 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2000 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2000 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2000 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2000 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2000 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2000 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2000 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2000 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2000 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2001 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2001 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2001 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2001 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2001 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2001 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2001 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2001 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2001 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2001 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2001 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2001 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2001 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2001 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2001 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2001 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2001 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2001 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2001 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2001 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2001 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2002 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2002 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2002 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2002 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2002 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2002 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2002 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2002 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2002 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2002 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2002 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2002 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2002 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2002 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2002 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2002 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2002 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2002 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2002 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2002 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2002 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2003 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2003 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2003 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2003 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2003 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2003 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2003 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2003 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2003 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2003 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2003 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2003 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2003 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2003 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2003 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2003 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2003 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2003 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2003 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2003 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2003 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2004 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2004 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2004 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2004 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2004 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2004 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2004 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2004 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2004 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2004 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2004 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2004 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2004 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2004 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2004 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2004 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2004 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2004 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2004 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2004 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2004 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2005 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2005 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2005 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2005 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2005 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2005 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2005 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2005 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2005 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2005 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2005 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2005 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2005 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2005 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2005 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2005 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2005 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2005 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2005 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2005 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2005 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2006 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2006 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2006 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2006 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2006 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2006 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2006 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2006 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2006 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2006 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2006 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2006 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2006 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2006 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2006 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2006 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2006 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2006 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2006 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2006 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2006 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2007 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2007 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2007 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2007 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2007 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2007 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2007 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2007 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2007 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2007 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2007 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2007 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2007 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2007 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2007 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2007 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2007 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2007 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2007 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2007 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2007 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2008 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2008 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2008 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2008 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2008 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2008 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2008 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2008 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2008 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2008 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2008 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2008 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2008 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2008 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2008 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2008 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2008 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2008 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2008 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2008 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2008 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2009 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2009 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2009 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2009 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2009 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2009 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2009 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2009 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2009 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2009 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2009 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2009 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2009 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2009 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2009 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2009 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2009 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2009 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2009 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2009 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2009 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2010 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2010 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2010 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2010 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2010 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2010 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2010 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2010 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2010 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2010 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2010 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2010 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2010 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2010 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2010 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2010 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2010 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2010 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2010 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2010 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2010 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2011 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2011 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2011 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2011 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2011 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2011 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2011 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2011 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2011 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2011 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2011 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2011 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2011 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2011 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2011 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2011 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2011 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2011 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2011 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2011 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2011 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2012 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2012 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2012 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2012 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2012 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2012 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2012 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2012 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2012 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2012 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2012 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2012 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2012 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2012 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2012 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2012 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2012 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2012 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2012 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2012 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2012 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2013 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2013 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2013 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2013 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2013 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2013 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2013 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2013 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2013 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2013 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2013 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2013 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2013 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2013 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2013 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2013 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2013 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2013 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2013 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2013 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2013 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2014 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2014 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2014 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2014 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2014 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2014 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2014 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2014 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2014 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2014 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2014 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2014 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2014 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2014 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2014 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2014 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2014 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2014 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2014 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2014 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2014 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2015 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2015 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2015 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2015 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2015 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2015 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2015 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2015 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2015 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2015 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2015 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2015 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2015 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2015 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2015 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2015 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2015 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2015 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2015 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2015 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2015 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2016 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2016 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2016 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2016 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2016 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2016 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2016 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2016 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2016 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2016 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2016 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2016 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2016 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2016 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2016 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2016 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2016 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2016 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2016 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2016 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2016 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2017 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2017 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2017 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2017 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2017 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2017 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2017 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2017 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2017 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2017 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2017 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2017 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2017 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2017 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2017 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2017 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2017 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2017 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2017 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2017 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2017 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2018 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2018 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2018 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2018 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2018 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2018 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2018 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2018 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2018 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2018 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2018 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2018 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2018 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2018 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2018 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2018 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2018 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2018 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2018 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2018 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2018 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2019 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2019 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2019 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2019 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2019 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2019 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2019 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2019 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2019 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2019 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2019 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2019 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2019 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2019 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2019 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2019 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2019 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2019 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2019 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2019 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2019 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2020 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2020 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2020 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2020 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2020 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2020 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2020 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2020 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2020 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2020 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2020 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2020 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2020 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2020 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2020 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2020 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2020 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2020 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2020 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2020 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2020 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2021 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2021 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2021 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2021 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2021 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2021 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2021 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2021 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2021 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2021 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2021 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2021 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2021 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2021 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2021 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2021 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2021 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2021 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2021 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2021 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2021 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2022 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2022 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2022 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2022 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2022 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2022 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2022 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2022 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2022 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2022 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2022 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2022 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2022 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2022 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2022 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2022 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2022 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2022 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2022 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2022 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2022 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2023 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2023 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2023 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2023 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2023 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2023 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2023 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2023 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2023 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2023 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2023 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2023 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2023 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2023 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2023 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2023 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2023 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2023 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2023 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2023 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2023 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2024 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2024 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2024 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2024 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2024 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2024 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2024 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2024 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2024 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2024 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2024 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2024 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2024 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2024 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2024 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2024 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2024 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2024 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2024 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2024 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2024 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2025 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2025 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2025 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2025 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2025 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2025 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2025 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2025 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2025 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2025 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2025 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2025 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2025 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2025 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2025 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2025 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2025 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2025 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2025 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2025 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2025 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2026 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2026 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2026 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2026 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2026 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2026 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2026 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2026 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2026 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2026 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2026 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2026 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2026 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2026 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2026 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2026 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2026 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2026 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2026 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2026 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2026 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2027 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2027 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2027 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2027 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2027 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2027 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2027 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2027 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2027 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2027 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2027 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2027 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2027 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2027 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2027 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2027 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2027 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2027 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2027 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2027 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2027 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2028 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2028 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2028 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2028 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2028 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2028 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2028 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2028 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2028 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2028 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2028 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2028 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2028 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2028 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2028 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2028 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2028 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2028 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2028 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2028 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2028 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2029 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2029 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2029 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2029 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2029 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2029 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2029 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2029 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2029 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2029 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2029 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2029 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2029 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2029 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2029 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2029 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2029 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2029 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2029 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2029 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2029 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2030 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2030 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2030 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2030 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2030 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2030 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2030 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2030 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2030 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2030 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2030 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2030 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2030 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2030 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2030 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2030 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2030 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2030 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2030 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2030 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2030 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2031 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2031 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2031 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2031 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2031 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2031 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2031 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2031 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2031 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2031 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2031 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2031 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2031 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2031 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2031 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2031 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2031 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2031 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2031 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2031 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2031 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2032 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2032 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2032 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2032 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2032 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2032 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2032 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2032 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2032 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2032 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2032 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2032 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2032 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2032 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2032 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2032 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2032 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2032 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2032 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2032 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2032 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2033 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2033 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2033 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2033 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2033 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2033 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2033 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2033 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2033 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2033 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2033 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2033 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2033 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2033 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2033 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2033 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2033 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2033 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2033 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2033 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2033 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2034 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2034 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2034 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2034 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2034 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2034 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2034 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2034 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2034 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2034 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2034 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2034 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2034 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2034 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2034 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2034 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2034 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2034 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2034 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2034 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2034 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2035 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2035 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2035 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2035 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2035 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2035 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2035 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2035 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2035 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2035 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2035 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2035 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2035 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2035 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2035 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2035 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2035 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2035 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2035 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2035 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2035 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2036 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2036 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2036 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2036 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2036 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2036 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2036 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2036 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2036 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2036 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2036 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2036 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2036 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2036 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2036 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2036 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2036 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2036 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2036 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2036 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2036 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2037 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2037 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2037 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2037 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2037 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2037 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2037 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2037 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2037 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2037 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2037 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2037 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2037 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2037 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2037 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2037 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2037 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2037 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2037 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2037 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2037 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2038 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2038 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2038 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2038 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2038 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2038 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2038 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2038 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2038 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2038 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2038 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2038 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2038 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2038 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2038 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2038 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2038 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2038 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2038 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2038 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2038 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2039 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2039 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2039 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2039 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2039 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2039 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2039 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2039 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2039 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2039 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2039 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2039 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2039 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2039 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2039 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2039 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2039 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2039 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2039 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2039 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2039 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2040 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2040 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2040 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2040 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2040 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2040 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2040 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2040 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2040 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2040 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2040 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2040 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2040 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2040 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2040 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2040 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2040 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2040 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2040 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2040 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2040 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2041 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2041 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2041 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2041 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2041 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2041 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2041 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2041 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2041 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2041 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2041 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2041 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2041 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2041 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2041 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2041 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2041 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2041 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2041 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2041 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2041 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2042 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2042 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2042 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2042 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2042 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2042 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2042 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2042 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2042 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2042 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2042 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2042 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2042 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2042 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2042 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2042 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2042 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2042 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2042 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2042 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2042 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2043 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2043 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2043 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2043 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2043 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2043 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2043 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2043 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2043 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2043 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2043 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2043 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2043 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2043 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2043 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2043 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2043 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2043 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2043 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2043 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2043 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2044 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2044 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2044 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2044 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2044 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2044 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2044 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2044 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2044 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2044 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2044 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2044 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2044 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2044 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2044 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2044 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2044 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2044 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2044 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2044 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2044 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2045 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2045 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2045 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2045 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2045 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2045 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2045 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2045 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2045 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2045 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2045 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2045 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2045 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2045 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2045 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2045 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2045 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2045 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2045 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2045 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2045 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2046 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2046 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2046 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2046 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2046 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2046 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2046 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2046 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2046 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2046 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2046 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2046 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2046 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2046 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2046 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2046 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2046 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2046 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2046 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2046 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2046 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2047 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2047 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2047 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2047 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2047 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2047 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2047 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2047 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2047 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2047 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2047 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2047 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2047 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2047 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2047 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2047 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2047 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2047 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2047 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2047 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2047 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2048 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2048 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2048 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2048 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2048 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2048 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2048 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2048 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2048 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2048 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2048 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2048 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2048 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2048 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2048 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2048 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2048 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2048 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2048 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2048 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2048 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2049 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2049 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2049 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2049 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2049 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2049 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2049 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2049 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2049 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2049 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2049 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2049 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2049 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2049 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2049 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2049 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2049 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2049 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2049 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2049 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2049 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2050 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2050 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2050 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2050 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2050 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2050 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2050 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2050 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2050 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2050 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2050 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2050 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2050 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2050 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2050 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2050 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2050 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2050 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2050 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2050 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2050 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2051 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2051 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2051 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2051 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2051 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2051 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2051 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2051 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2051 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2051 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2051 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2051 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2051 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2051 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2051 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2051 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2051 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2051 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2051 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2051 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2051 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2052 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2052 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2052 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2052 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2052 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2052 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2052 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2052 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2052 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2052 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2052 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2052 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2052 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2052 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2052 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2052 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2052 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2052 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2052 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2052 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2052 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2053 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2053 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2053 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2053 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2053 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2053 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2053 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2053 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2053 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2053 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2053 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2053 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2053 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2053 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2053 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2053 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2053 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2053 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2053 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2053 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2053 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2054 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2054 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2054 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2054 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2054 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2054 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2054 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2054 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2054 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2054 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2054 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2054 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2054 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2054 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2054 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2054 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2054 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2054 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2054 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2054 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2054 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2055 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2055 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2055 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2055 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2055 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2055 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2055 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2055 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2055 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2055 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2055 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2055 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2055 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2055 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2055 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2055 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2055 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2055 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2055 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2055 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2055 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2056 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2056 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2056 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2056 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2056 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2056 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2056 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2056 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2056 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2056 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2056 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2056 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2056 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2056 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2056 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2056 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2056 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2056 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2056 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2056 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2056 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2057 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2057 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2057 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2057 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2057 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2057 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2057 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2057 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2057 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2057 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2057 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2057 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2057 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2057 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2057 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2057 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2057 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2057 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2057 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2057 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2057 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2058 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2058 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2058 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2058 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2058 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2058 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2058 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2058 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2058 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2058 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2058 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2058 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2058 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2058 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2058 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2058 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2058 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2058 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2058 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2058 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2058 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2059 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2059 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2059 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2059 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2059 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2059 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2059 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2059 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2059 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2059 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2059 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2059 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2059 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2059 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2059 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2059 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2059 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2059 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2059 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2059 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2059 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2060 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2060 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2060 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2060 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2060 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2060 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2060 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2060 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2060 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2060 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2060 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2060 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2060 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2060 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2060 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2060 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2060 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2060 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2060 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2060 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2060 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2061 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2061 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2061 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2061 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2061 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2061 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2061 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2061 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2061 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2061 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2061 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2061 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2061 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2061 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2061 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2061 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2061 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2061 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2061 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2061 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2061 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2062 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2062 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2062 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2062 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2062 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2062 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2062 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2062 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2062 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2062 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2062 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2062 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2062 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2062 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2062 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2062 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2062 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2062 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2062 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2062 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2062 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2063 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2063 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2063 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2063 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2063 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2063 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2063 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2063 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2063 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2063 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2063 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2063 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2063 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2063 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2063 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2063 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2063 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2063 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2063 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2063 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2063 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2064 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2064 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2064 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2064 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2064 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2064 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2064 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2064 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2064 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2064 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2064 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2064 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2064 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2064 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2064 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2064 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2064 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2064 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2064 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2064 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2064 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2065 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2065 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2065 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2065 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2065 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2065 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2065 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2065 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2065 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2065 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2065 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2065 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2065 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2065 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2065 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2065 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2065 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2065 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2065 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2065 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2065 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2066 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2066 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2066 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2066 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2066 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2066 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2066 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2066 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2066 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2066 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2066 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2066 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2066 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2066 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2066 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2066 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2066 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2066 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2066 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2066 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2066 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2067 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2067 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2067 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2067 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2067 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2067 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2067 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2067 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2067 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2067 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2067 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2067 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2067 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2067 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2067 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2067 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2067 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2067 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2067 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2067 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2067 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2068 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2068 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2068 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2068 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2068 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2068 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2068 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2068 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2068 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2068 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2068 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2068 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2068 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2068 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2068 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2068 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2068 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2068 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2068 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2068 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2068 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2069 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2069 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2069 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2069 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2069 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2069 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2069 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2069 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2069 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2069 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2069 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2069 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2069 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2069 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2069 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2069 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2069 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2069 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2069 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2069 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2069 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2070 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2070 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2070 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2070 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2070 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2070 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2070 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2070 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2070 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2070 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2070 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2070 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2070 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2070 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2070 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2070 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2070 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2070 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2070 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2070 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2070 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2071 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2071 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2071 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2071 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2071 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2071 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2071 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2071 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2071 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2071 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2071 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2071 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2071 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2071 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2071 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2071 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2071 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2071 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2071 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2071 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2071 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2072 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2072 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2072 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2072 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2072 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2072 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2072 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2072 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2072 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2072 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2072 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2072 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2072 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2072 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2072 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2072 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2072 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2072 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2072 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2072 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2072 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2073 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2073 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2073 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2073 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2073 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2073 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2073 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2073 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2073 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2073 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2073 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2073 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2073 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2073 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2073 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2073 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2073 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2073 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2073 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2073 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2073 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2074 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2074 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2074 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2074 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2074 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2074 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2074 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2074 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2074 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2074 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2074 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2074 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2074 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2074 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2074 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2074 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2074 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2074 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2074 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2074 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2074 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2075 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2075 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2075 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2075 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2075 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2075 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2075 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2075 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2075 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2075 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2075 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2075 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2075 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2075 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2075 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2075 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2075 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2075 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2075 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2075 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2075 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2137 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2137 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2137 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2137 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2137 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2137 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2137 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2137 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2137 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2137 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2137 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2137 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2137 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2137 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2137 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2137 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2137 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2137 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2137 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2137 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2137 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2138 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2138 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2138 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2138 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2138 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2138 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2138 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2138 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2138 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2138 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2138 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2138 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2138 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2138 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2138 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2138 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2138 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2138 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2138 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2138 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2138 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2139 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2139 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2139 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2139 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2139 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2139 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2139 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2139 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2139 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2139 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2139 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2139 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2139 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2139 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2139 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2139 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2139 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2139 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2139 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2139 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2139 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2140 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2140 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2140 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2140 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2140 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2140 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2140 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2140 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2140 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2140 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2140 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2140 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2140 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2140 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2140 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2140 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2140 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2140 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2140 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2140 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2140 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2141 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2141 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2141 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2141 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2141 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2141 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2141 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2141 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2141 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2141 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2141 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2141 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2141 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2141 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2141 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2141 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2141 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2141 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2141 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2141 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2141 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2142 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2142 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2142 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2142 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2142 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2142 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2142 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2142 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2142 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2142 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2142 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2142 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2142 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2142 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2142 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2142 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2142 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2142 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2142 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2142 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2142 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2143 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2143 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2143 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2143 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2143 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2143 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2143 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2143 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2143 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2143 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2143 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2143 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2143 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2143 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2143 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2143 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2143 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2143 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2143 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2143 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2143 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2144 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2144 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2144 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2144 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2144 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2144 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2144 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2144 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2144 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2144 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2144 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2144 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2144 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2144 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2144 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2144 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2144 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2144 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2144 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2144 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2144 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2145 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2145 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2145 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2145 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2145 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2145 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2145 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2145 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2145 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2145 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2145 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2145 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2145 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2145 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2145 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2145 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2145 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2145 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2145 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2145 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2145 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2146 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2146 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2146 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2146 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2146 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2146 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2146 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2146 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2146 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2146 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2146 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2146 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2146 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2146 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2146 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2146 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2146 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2146 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2146 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2146 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2146 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2147 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2147 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2147 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2147 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2147 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2147 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2147 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2147 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2147 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2147 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2147 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2147 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2147 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2147 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2147 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2147 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2147 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2147 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2147 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2147 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2147 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2148 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2148 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2148 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2148 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2148 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2148 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2148 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2148 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2148 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2148 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2148 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2148 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2148 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2148 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2148 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2148 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2148 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2148 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2148 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2148 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2148 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2149 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2149 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2149 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2149 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2149 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2149 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2149 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2149 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2149 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2149 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2149 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2149 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2149 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2149 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2149 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2149 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2149 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2149 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2149 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2149 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2149 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2150 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2150 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2150 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2150 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2150 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2150 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2150 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2150 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2150 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2150 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2150 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2150 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2150 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2150 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2150 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2150 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2150 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2150 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2150 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2150 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2150 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2151 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2151 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2151 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2151 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2151 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2151 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2151 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2151 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2151 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2151 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2151 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2151 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2151 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2151 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2151 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2151 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2151 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2151 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2151 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2151 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2151 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2152 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2152 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2152 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2152 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2152 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2152 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2152 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2152 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2152 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2152 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2152 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2152 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2152 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2152 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2152 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2152 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2152 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2152 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2152 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2152 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2152 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2153 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2153 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2153 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2153 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2153 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2153 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2153 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2153 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2153 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2153 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2153 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2153 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2153 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2153 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2153 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2153 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2153 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2153 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2153 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2153 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2153 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2154 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2154 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2154 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2154 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2154 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2154 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2154 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2154 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2154 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2154 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2154 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2154 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2154 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2154 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2154 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2154 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2154 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2154 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2154 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2154 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2154 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2155 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2155 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2155 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2155 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2155 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2155 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2155 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2155 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2155 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2155 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2155 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2155 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2155 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2155 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2155 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2155 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2155 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2155 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2155 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2155 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2155 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2156 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2156 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2156 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2156 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2156 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2156 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2156 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2156 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2156 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2156 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2156 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2156 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2156 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2156 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2156 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2156 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2156 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2156 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2156 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2156 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2156 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2157 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2157 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2157 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2157 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2157 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2157 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2157 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2157 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2157 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2157 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2157 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2157 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2157 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2157 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2157 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2157 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2157 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2157 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2157 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2157 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2157 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2158 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2158 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2158 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2158 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2158 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2158 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2158 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2158 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2158 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2158 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2158 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2158 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2158 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2158 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2158 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2158 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2158 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2158 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2158 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2158 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2158 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2159 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2159 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2159 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2159 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2159 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2159 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2159 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2159 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2159 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2159 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2159 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2159 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2159 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2159 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2159 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2159 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2159 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2159 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2159 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2159 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2159 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2160 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2160 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2160 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2160 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2160 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2160 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2160 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2160 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2160 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2160 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2160 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2160 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2160 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2160 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2160 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2160 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2160 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2160 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2160 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2160 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2160 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2161 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2161 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2161 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2161 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2161 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2161 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2161 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2161 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2161 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2161 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2161 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2161 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2161 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2161 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2161 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2161 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2161 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2161 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2161 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2161 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2161 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2162 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2162 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2162 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2162 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2162 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2162 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2162 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2162 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2162 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2162 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2162 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2162 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2162 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2162 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2162 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2162 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2162 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2162 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2162 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2162 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2162 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2163 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2163 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2163 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2163 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2163 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2163 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2163 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2163 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2163 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2163 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2163 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2163 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2163 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2163 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2163 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2163 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2163 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2163 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2163 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2163 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2163 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2164 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2164 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2164 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2164 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2164 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2164 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2164 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2164 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2164 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2164 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2164 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2164 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2164 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2164 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2164 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2164 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2164 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2164 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2164 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2164 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2164 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2165 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2165 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2165 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2165 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2165 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2165 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2165 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2165 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2165 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2165 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2165 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2165 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2165 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2165 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2165 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2165 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2165 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2165 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2165 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2165 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2165 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2166 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2166 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2166 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2166 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2166 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2166 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2166 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2166 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2166 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2166 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2166 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2166 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2166 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2166 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2166 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2166 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2166 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2166 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2166 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2166 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2166 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2167 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2167 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2167 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2167 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2167 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2167 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2167 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2167 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2167 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2167 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2167 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2167 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2167 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2167 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2167 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2167 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2167 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2167 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2167 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2167 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2167 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2168 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2168 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2168 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2168 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2168 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2168 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2168 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2168 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2168 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2168 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2168 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2168 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2168 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2168 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2168 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2168 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2168 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2168 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2168 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2168 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2168 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2171 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2171 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2171 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2171 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2171 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2171 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2171 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2171 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2171 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2171 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2171 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2171 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2171 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2171 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2171 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2171 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2171 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2171 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2171 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2171 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2171 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2172 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2172 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2172 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2172 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2172 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2172 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2172 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2172 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2172 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2172 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2172 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2172 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2172 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2172 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2172 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2172 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2172 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2172 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2172 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2172 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2172 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2173 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2173 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2173 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2173 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2173 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2173 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2173 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2173 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2173 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2173 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2173 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2173 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2173 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2173 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2173 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2173 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2173 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2173 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2173 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2173 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2173 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2174 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2174 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2174 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2174 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2174 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2174 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2174 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2174 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2174 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2174 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2174 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2174 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2174 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2174 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2174 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2174 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2174 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2174 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2174 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2174 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2174 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2175 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2175 and a VOY201 capsid, in some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2175 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2175 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2175 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2175 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2175 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2175 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2175 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2175 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2175 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2175 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2175 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2175 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2175 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2175 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2175 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2175 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2175 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2175 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2175 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2176 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2176 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2176 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2176 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2176 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2176 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2176 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2176 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2176 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2176 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2176 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2176 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2176 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2176 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2176 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2176 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2176 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2176 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2176 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2176 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2176 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2177 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2177 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2177 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2177 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2177 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2177 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2177 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2177 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2177 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2177 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2177 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2177 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2177 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2177 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2177 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2177 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2177 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2177 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2177 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2177 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2177 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2178 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2178 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2178 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2178 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2178 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2178 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2178 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2178 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2178 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2178 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2178 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2178 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2178 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2178 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2178 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2178 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2178 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2178 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2178 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2178 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2178 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2179 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2179 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2179 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2179 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2179 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2179 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2179 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2179 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2179 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2179 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2179 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2179 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2179 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2179 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2179 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2179 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2179 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2179 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2179 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2179 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2179 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2180 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2180 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2180 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2180 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2180 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2180 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2180 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2180 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2180 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2180 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2180 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2180 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2180 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2180 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2180 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2180 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2180 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2180 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2180 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2180 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2180 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2181 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2181 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2181 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2181 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2181 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2181 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2181 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2181 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2181 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2181 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2181 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2181 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2181 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2181 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2181 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2181 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2181 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2181 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2181 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2181 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2181 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2182 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2182 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2182 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2182 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2182 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2182 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2182 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2182 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2182 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2182 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2182 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2182 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2182 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2182 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2182 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2182 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2182 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2182 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2182 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2182 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2182 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2183 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2183 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2183 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2183 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2183 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2183 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2183 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2183 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2183 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2183 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2183 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2183 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2183 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2183 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2183 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2183 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2183 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2183 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2183 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2183 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2183 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2184 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2184 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2184 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2184 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2184 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2184 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2184 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2184 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2184 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2184 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2184 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2184 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2184 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2184 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2184 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2184 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2184 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2184 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2184 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2184 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2184 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2185 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2185 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2185 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2185 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2185 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2185 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2185 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2185 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2185 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2185 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2185 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2185 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2185 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2185 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2185 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2185 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2185 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2185 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2185 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2185 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2185 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2186 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2186 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2186 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2186 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2186 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2186 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2186 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2186 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2186 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2186 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2186 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2186 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2186 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2186 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2186 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2186 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2186 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2186 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2186 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2186 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2186 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2187 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2187 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2187 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2187 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2187 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2187 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2187 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2187 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2187 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2187 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2187 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2187 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2187 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2187 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2187 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2187 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2187 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2187 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2187 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2187 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2187 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2188 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2188 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2188 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2188 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2188 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2188 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2188 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2188 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2188 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2188 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2188 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2188 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2188 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2188 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2188 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2188 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2188 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2188 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2188 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2188 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2188 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2189 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2189 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2189 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2189 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2189 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2189 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2189 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2189 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2189 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2189 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2189 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2189 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2189 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2189 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2189 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2189 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2189 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2189 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2189 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2189 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2189 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2190 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2190 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2190 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2190 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2190 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2190 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2190 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2190 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2190 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2190 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2190 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2190 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2190 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2190 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2190 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2190 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2190 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2190 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2190 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2190 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2190 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2191 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2191 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2191 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2191 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2191 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2191 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2191 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2191 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2191 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2191 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2191 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2191 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2191 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2191 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2191 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2191 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2191 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2191 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2191 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2191 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2191 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2192 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2192 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2192 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2192 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2192 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2192 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2192 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2192 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2192 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2192 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2192 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2192 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2192 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2192 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2192 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2192 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2192 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2192 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2192 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2192 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2192 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2193 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2193 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2193 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2193 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2193 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2193 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2193 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2193 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2193 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2193 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2193 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2193 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2193 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2193 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2193 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2193 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2193 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2193 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2193 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2193 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2193 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2194 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2194 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2194 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2194 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2194 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2194 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2194 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2194 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2194 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2194 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2194 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2194 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2194 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2194 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2194 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2194 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2194 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2194 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2194 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2194 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2194 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2195 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2195 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2195 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2195 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2195 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2195 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2195 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2195 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2195 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2195 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2195 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2195 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2195 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2195 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2195 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2195 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2195 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2195 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2195 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2195 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2195 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2196 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2196 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2196 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2196 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2196 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2196 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2196 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2196 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2196 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2196 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2196 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2196 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2196 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2196 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2196 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2196 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2196 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2196 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2196 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2196 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2196 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2197 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2197 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2197 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2197 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2197 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2197 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2197 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2197 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2197 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2197 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2197 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2197 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2197 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2197 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2197 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2197 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2197 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2197 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2197 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2197 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2197 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2198 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2198 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2198 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2198 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2198 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2198 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2198 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2198 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2198 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2198 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2198 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2198 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2198 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2198 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2198 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2198 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2198 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2198 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2198 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2198 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2198 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2199 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2199 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2199 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2199 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2199 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2199 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2199 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2199 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2199 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2199 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2199 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2199 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2199 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2199 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2199 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2199 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2199 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2199 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2199 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2199 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2199 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2200 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2200 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2200 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2200 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2200 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2200 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2200 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2200 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2200 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2200 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2200 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2200 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2200 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2200 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2200 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2200 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2200 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2200 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2200 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2200 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2200 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2201 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2201 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2201 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2201 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2201 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2201 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2201 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2201 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2201 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2201 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2201 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2201 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2201 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2201 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2201 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2201 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2201 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2201 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2201 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2201 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2201 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2202 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2202 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2202 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2202 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2202 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2202 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2202 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2202 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2202 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2202 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2202 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2202 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2202 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2202 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2202 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2202 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2202 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2202 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2202 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2202 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2202 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2203 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2203 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2203 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2203 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2203 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2203 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2203 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2203 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2203 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2203 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2203 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2203 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2203 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2203 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2203 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2203 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2203 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2203 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2203 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2203 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2203 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2204 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2204 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2204 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2204 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2204 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2204 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2204 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2204 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2204 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2204 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2204 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2204 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2204 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2204 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2204 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2204 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2204 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2204 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2204 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2204 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2204 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2205 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2205 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2205 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2205 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2205 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2205 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2205 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2205 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2205 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2205 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2205 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2205 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2205 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2205 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2205 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2205 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2205 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2205 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2205 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2205 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2205 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2206 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2206 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2206 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2206 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2206 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2206 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2206 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2206 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2206 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2206 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2206 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2206 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2206 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2206 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2206 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2206 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2206 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2206 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2206 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2206 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2206 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2207 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2207 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2207 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2207 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2207 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2207 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2207 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2207 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2207 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2207 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2207 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2207 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2207 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2207 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2207 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2207 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2207 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2207 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2207 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2207 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2207 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2208 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2208 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2208 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2208 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2208 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2208 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2208 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2208 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2208 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2208 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2208 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2208 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2208 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2208 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2208 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2208 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2208 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2208 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2208 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2208 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2208 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2209 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2209 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2209 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2209 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2209 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2209 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2209 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2209 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2209 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2209 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2209 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2209 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2209 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2209 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2209 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2209 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2209 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2209 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2209 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2209 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2209 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2210 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2210 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2210 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2210 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2210 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2210 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2210 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2210 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2210 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2210 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2210 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2210 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2210 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2210 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2210 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2210 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2210 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2210 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2210 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2210 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2210 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2211 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2211 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2211 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2211 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2211 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2211 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2211 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2211 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2211 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2211 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2211 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2211 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2211 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2211 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2211 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2211 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2211 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2211 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2211 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2211 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2211 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2212 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2212 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2212 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2212 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2212 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2212 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2212 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2212 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2212 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2212 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2212 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2212 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2212 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2212 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2212 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2212 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2212 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2212 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2212 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2212 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2212 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2213 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2213 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2213 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2213 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2213 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2213 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2213 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2213 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2213 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2213 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2213 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2213 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2213 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2213 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2213 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2213 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2213 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2213 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2213 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2213 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2213 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2214 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2214 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2214 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2214 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2214 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2214 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2214 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2214 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2214 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2214 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2214 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2214 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2214 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2214 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2214 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2214 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2214 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2214 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2214 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2214 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2214 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2215 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2215 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2215 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2215 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2215 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2215 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2215 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2215 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2215 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2215 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2215 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2215 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2215 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2215 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2215 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2215 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2215 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2215 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2215 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2215 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2215 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2216 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2216 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2216 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2216 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2216 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2216 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2216 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2216 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2216 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2216 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2216 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2216 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2216 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2216 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2216 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2216 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2216 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2216 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2216 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2216 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2216 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2217 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2217 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2217 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2217 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2217 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2217 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2217 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2217 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2217 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2217 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2217 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2217 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2217 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2217 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2217 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2217 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2217 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2217 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2217 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2217 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2217 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2218 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2218 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2218 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2218 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2218 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2218 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2218 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2218 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2218 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2218 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2218 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2218 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2218 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2218 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2218 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2218 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2218 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2218 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2218 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2218 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2218 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2219 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2219 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2219 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2219 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2219 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2219 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2219 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2219 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2219 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2219 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2219 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2219 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2219 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2219 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2219 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2219 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2219 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2219 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2219 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2219 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2219 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2220 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2220 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2220 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2220 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2220 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2220 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2220 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2220 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2220 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2220 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2220 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2220 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2220 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2220 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2220 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2220 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2220 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2220 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2220 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2220 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2220 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2221 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2221 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2221 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2221 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2221 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2221 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2221 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2221 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2221 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2221 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2221 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2221 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2221 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2221 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2221 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2221 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2221 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2221 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2221 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2221 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2221 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2222 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2222 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2222 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2222 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2222 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2222 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2222 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2222 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2222 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2222 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2222 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2222 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2222 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2222 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2222 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2222 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2222 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2222 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2222 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2222 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2222 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2223 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2223 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2223 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2223 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2223 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2223 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2223 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2223 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2223 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2223 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2223 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2223 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2223 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2223 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2223 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2223 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2223 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2223 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2223 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2223 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2223 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2224 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2224 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2224 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2224 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2224 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2224 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2224 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2224 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2224 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2224 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2224 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2224 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2224 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2224 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2224 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2224 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2224 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2224 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2224 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2224 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2224 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2225 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2225 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2225 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2225 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2225 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2225 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2225 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2225 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2225 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2225 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2225 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2225 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2225 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2225 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2225 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2225 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2225 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2225 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2225 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2225 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2225 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2226 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2226 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2226 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2226 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2226 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2226 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2226 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2226 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2226 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2226 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2226 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2226 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2226 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2226 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2226 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2226 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2226 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2226 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2226 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2226 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2226 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2227 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2227 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2227 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2227 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2227 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2227 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2227 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2227 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2227 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2227 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2227 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2227 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2227 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2227 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2227 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2227 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2227 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2227 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2227 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2227 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2227 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2228 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2228 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2228 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2228 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2228 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2228 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2228 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2228 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2228 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2228 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2228 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2228 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2228 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2228 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2228 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2228 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2228 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2228 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2228 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2228 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2228 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2229 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2229 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2229 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2229 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2229 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2229 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2229 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2229 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2229 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2229 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2229 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2229 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2229 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2229 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2229 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2229 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2229 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2229 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2229 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2229 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2229 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2230 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2230 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2230 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2230 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2230 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2230 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2230 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2230 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2230 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2230 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2230 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2230 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2230 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2230 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2230 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2230 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2230 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2230 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2230 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2230 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2230 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2231 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2231 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2231 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2231 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2231 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2231 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2231 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2231 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2231 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2231 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2231 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2231 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2231 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2231 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2231 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2231 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2231 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2231 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2231 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2231 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2231 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2232 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2232 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2232 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2232 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2232 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2232 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2232 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2232 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2232 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2232 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2232 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2232 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2232 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2232 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2232 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2232 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2232 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2232 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2232 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2232 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2232 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2233 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2233 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2233 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2233 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2233 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2233 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2233 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2233 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2233 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2233 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2233 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2233 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2233 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2233 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2233 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2233 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2233 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2233 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2233 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2233 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2233 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2234 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2234 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2234 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2234 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2234 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2234 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2234 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2234 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2234 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2234 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2234 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2234 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2234 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2234 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2234 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2234 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2234 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2234 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2234 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2234 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2234 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2235 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2235 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2235 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2235 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2235 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2235 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2235 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2235 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2235 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2235 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2235 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2235 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2235 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2235 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2235 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2235 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2235 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2235 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2235 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2235 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2235 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2236 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2236 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2236 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2236 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2236 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2236 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2236 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2236 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2236 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2236 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2236 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2236 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2236 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2236 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2236 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2236 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2236 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2236 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2236 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2236 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2236 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2237 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2237 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2237 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2237 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2237 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2237 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2237 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2237 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2237 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2237 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2237 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2237 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2237 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2237 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2237 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2237 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2237 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2237 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2237 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2237 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2237 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2260 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2260 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2260 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2260 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2260 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2260 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2260 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2260 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2260 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2260 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2260 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2260 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2260 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2260 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2260 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2260 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2260 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2260 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2260 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2260 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2260 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2261 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2261 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2261 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2261 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2261 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2261 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2261 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2261 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2261 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2261 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2261 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2261 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2261 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2261 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2261 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2261 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2261 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2261 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2261 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2261 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2261 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2262 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2262 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2262 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2262 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2262 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2262 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2262 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2262 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2262 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2262 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2262 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2262 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2262 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2262 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2262 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2262 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2262 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2262 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2262 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2262 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2262 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2263 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2263 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2263 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2263 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2263 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2263 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2263 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2263 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2263 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2263 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2263 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2263 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2263 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2263 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2263 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2263 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2263 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2263 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2263 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2263 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2263 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2264 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2264 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2264 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2264 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2264 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2264 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2264 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2264 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2264 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2264 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2264 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2264 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2264 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2264 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2264 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2264 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2264 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2264 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2264 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2264 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2264 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2265 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2265 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2265 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2265 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2265 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2265 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2265 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2265 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2265 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2265 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2265 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2265 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2265 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2265 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2265 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2265 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2265 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2265 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2265 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2265 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2265 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2266 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2266 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2266 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2266 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2266 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2266 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2266 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2266 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2266 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2266 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2266 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2266 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2266 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2266 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2266 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2266 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2266 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2266 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2266 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2266 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2266 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2267 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2267 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2267 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2267 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2267 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2267 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2267 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2267 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2267 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2267 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2267 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2267 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2267 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2267 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2267 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2267 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2267 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2267 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2267 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2267 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2267 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2268 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2268 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2268 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2268 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2268 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2268 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2268 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2268 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2268 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2268 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2268 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2268 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2268 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2268 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2268 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2268 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2268 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2268 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2268 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2268 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2268 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2269 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2269 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2269 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2269 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2269 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2269 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2269 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2269 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2269 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2269 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2269 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2269 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2269 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2269 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2269 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2269 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2269 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2269 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2269 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2269 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2269 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2270 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2270 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2270 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2270 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2270 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2270 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2270 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2270 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2270 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2270 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2270 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2270 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2270 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2270 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2270 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2270 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2270 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2270 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2270 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2270 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2270 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2271 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2271 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2271 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2271 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2271 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2271 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2271 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2271 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2271 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2271 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2271 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2271 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2271 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2271 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2271 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2271 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2271 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2271 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2271 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2271 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2271 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2272 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2272 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2272 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2272 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2272 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2272 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2272 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2272 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2272 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2272 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2272 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2272 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2272 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2272 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2272 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2272 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2272 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2272 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2272 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2272 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2272 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2273 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2273 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2273 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2273 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2273 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2273 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2273 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2273 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2273 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2273 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2273 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2273 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2273 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2273 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2273 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2273 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2273 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2273 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2273 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2273 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2273 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2274 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2274 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2274 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2274 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2274 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2274 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2274 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2274 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2274 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2274 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2274 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2274 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2274 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2274 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2274 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2274 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2274 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2274 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2274 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2274 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2274 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2275 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2275 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2275 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2275 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2275 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2275 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2275 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2275 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2275 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2275 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2275 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2275 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2275 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2275 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2275 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2275 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2275 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2275 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2275 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2275 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2275 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2276 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2276 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2276 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2276 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2276 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2276 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2276 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2276 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2276 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2276 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2276 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2276 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2276 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2276 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2276 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2276 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2276 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2276 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2276 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2276 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2276 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2277 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2277 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2277 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2277 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2277 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2277 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2277 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2277 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2277 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2277 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2277 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2277 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2277 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2277 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2277 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2277 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2277 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2277 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2277 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2277 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2277 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2278 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2278 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2278 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2278 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2278 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2278 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2278 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2278 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2278 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2278 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2278 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2278 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2278 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2278 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2278 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2278 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2278 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2278 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2278 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2278 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2278 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2279 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2279 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2279 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2279 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2279 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2279 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2279 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2279 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2279 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2279 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2279 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2279 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2279 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2279 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2279 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2279 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2279 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2279 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2279 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2279 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2279 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2280 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2280 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2280 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2280 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2280 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2280 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2280 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2280 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2280 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2280 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2280 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2280 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2280 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2280 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2280 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2280 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2280 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2280 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2280 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2280 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2280 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2281 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2281 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2281 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2281 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2281 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2281 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2281 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2281 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2281 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2281 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2281 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2281 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2281 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2281 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2281 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2281 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2281 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2281 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2281 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2281 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2281 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2282 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2282 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2282 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2282 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2282 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2282 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2282 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2282 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2282 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2282 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2282 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2282 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2282 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2282 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2282 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2282 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2282 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2282 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2282 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2282 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2282 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2283 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2283 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2283 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2283 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2283 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2283 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2283 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2283 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2283 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2283 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2283 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2283 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2283 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2283 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2283 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2283 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2283 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2283 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2283 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2283 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2283 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2284 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2284 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2284 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2284 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2284 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2284 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2284 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2284 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2284 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2284 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2284 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2284 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2284 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2284 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2284 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2284 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2284 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2284 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2284 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2284 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2284 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2285 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2285 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2285 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2285 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2285 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2285 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2285 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2285 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2285 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2285 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2285 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2285 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2285 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2285 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2285 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2285 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2285 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2285 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2285 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2285 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2285 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2286 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2286 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2286 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2286 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2286 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2286 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2286 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2286 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2286 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2286 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2286 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2286 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2286 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2286 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2286 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2286 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2286 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2286 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2286 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2286 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2286 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2287 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2287 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2287 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2287 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2287 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2287 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2287 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2287 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2287 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2287 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2287 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2287 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2287 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2287 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2287 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2287 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2287 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2287 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2287 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2287 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2287 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2288 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2288 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2288 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2288 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2288 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2288 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2288 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2288 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2288 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2288 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2288 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2288 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2288 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2288 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2288 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2288 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2288 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2288 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2288 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2288 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2288 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2289 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2289 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2289 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2289 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2289 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2289 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2289 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2289 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2289 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2289 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2289 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2289 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2289 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2289 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2289 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2289 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2289 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2289 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2289 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2289 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2289 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2290 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2290 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2290 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2290 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2290 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2290 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2290 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2290 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2290 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2290 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2290 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2290 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2290 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2290 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2290 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2290 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2290 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2290 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2290 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2290 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2290 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2291 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2291 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2291 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2291 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2291 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2291 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2291 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2291 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2291 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2291 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2291 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2291 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2291 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2291 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2291 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2291 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2291 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2291 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2291 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2291 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2291 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2292 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2292 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2292 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2292 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2292 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2292 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2292 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2292 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2292 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2292 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2292 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2292 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2292 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2292 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2292 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2292 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2292 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2292 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2292 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2292 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2292 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2293 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2293 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2293 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2293 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2293 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2293 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2293 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2293 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2293 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2293 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2293 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2293 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2293 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2293 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2293 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2293 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2293 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2293 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2293 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2293 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2293 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2294 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2294 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2294 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2294 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2294 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2294 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2294 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2294 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2294 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2294 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2294 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2294 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2294 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2294 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2294 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2294 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2294 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2294 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2294 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2294 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2294 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2295 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2295 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2295 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2295 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2295 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2295 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2295 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2295 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2295 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2295 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2295 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2295 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2295 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2295 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2295 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2295 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2295 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2295 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2295 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2295 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2295 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2296 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2296 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2296 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2296 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2296 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2296 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2296 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2296 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2296 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2296 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2296 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2296 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2296 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2296 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2296 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2296 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2296 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2296 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2296 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2296 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2296 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2297 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2297 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2297 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2297 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2297 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2297 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2297 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2297 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2297 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2297 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2297 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2297 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2297 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2297 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2297 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2297 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2297 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2297 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2297 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2297 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2297 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2298 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2298 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2298 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2298 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2298 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2298 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2298 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2298 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2298 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2298 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2298 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2298 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2298 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2298 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2298 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2298 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2298 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2298 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2298 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2298 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2298 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2299 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2299 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2299 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2299 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2299 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2299 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2299 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2299 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2299 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2299 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2299 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2299 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2299 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2299 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2299 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2299 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2299 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2299 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2299 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2299 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2299 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2300 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2300 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2300 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2300 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2300 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2300 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2300 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2300 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2300 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2300 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2300 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2300 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2300 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2300 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2300 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2300 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2300 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2300 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2300 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2300 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2300 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2301 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2301 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2301 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2301 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2301 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2301 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2301 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2301 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2301 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2301 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2301 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2301 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2301 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2301 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2301 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2301 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2301 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2301 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2301 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2301 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2301 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2302 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2302 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2302 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2302 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2302 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2302 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2302 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2302 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2302 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2302 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2302 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2302 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2302 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2302 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2302 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2302 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2302 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2302 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2302 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2302 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2302 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2303 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2303 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2303 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2303 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2303 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2303 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2303 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2303 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2303 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2303 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2303 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2303 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2303 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2303 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2303 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2303 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2303 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2303 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2303 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2303 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2303 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2304 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2304 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2304 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2304 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2304 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2304 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2304 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2304 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2304 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2304 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2304 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2304 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2304 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2304 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2304 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2304 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2304 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2304 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2304 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2304 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2304 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2305 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2305 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2305 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2305 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2305 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2305 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2305 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2305 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2305 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2305 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2305 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2305 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2305 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2305 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2305 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2305 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2305 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2305 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2305 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2305 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2305 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2306 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2306 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2306 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2306 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2306 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2306 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2306 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2306 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2306 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2306 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2306 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2306 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2306 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2306 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2306 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2306 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2306 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2306 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2306 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2306 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2306 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2307 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2307 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2307 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2307 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2307 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2307 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2307 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2307 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2307 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2307 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2307 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2307 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2307 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2307 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2307 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2307 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2307 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2307 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2307 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2307 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2307 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2308 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2308 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2308 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2308 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2308 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2308 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2308 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2308 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2308 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2308 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2308 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2308 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2308 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2308 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2308 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2308 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2308 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2308 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2308 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2308 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2308 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2309 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2309 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2309 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2309 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2309 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2309 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2309 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2309 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2309 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2309 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2309 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2309 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2309 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2309 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2309 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2309 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2309 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2309 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2309 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2309 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2309 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2310 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2310 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2310 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2310 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2310 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2310 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2310 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2310 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2310 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2310 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2310 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2310 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2310 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2310 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2310 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2310 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2310 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2310 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2310 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2310 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2310 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2311 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2311 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2311 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2311 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2311 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2311 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2311 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2311 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2311 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2311 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2311 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2311 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2311 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2311 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2311 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2311 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2311 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2311 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2311 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2311 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2311 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2312 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2312 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2312 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2312 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2312 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2312 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2312 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2312 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2312 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2312 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2312 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2312 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2312 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2312 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2312 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2312 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2312 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2312 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2312 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2312 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2312 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2313 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2313 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2313 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2313 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2313 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2313 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2313 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2313 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2313 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2313 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2313 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2313 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2313 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2313 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2313 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2313 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2313 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2313 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2313 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2313 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2313 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2314 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2314 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2314 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2314 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2314 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2314 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2314 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2314 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2314 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2314 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2314 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2314 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2314 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2314 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2314 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2314 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2314 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2314 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2314 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2314 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2314 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2315 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2315 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2315 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2315 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2315 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2315 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2315 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2315 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2315 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2315 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2315 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2315 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2315 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2315 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2315 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2315 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2315 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2315 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2315 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2315 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2315 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2316 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2316 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2316 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2316 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2316 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2316 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2316 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2316 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2316 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2316 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2316 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2316 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2316 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2316 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2316 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2316 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2316 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2316 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2316 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2316 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2316 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2317 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2317 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2317 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2317 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2317 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2317 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2317 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2317 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2317 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2317 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2317 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2317 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2317 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2317 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2317 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2317 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2317 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2317 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2317 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2317 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2317 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2318 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2318 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2318 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2318 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2318 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2318 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2318 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2318 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2318 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2318 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2318 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2318 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2318 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2318 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2318 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2318 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2318 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2318 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2318 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2318 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2318 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2319 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2319 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2319 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2319 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2319 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2319 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2319 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2319 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2319 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2319 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2319 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2319 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2319 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2319 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2319 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2319 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2319 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2319 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2319 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2319 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2319 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2320 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2320 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2320 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2320 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2320 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2320 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2320 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2320 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2320 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2320 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2320 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2320 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2320 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2320 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2320 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2320 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2320 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2320 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2320 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2320 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2320 and a capsid comprising SEQ ID NO: 2871.

In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2321 and a VOY101 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2321 and a VOY201 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2321 and an AAV9 capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2321 and an AAV9K449R capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2321 and an AAVPHP.B capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2321 and an AAVPHP.N capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2321 and an AAV2 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2321 and an AAV2/3 variant capsid. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2321 and a capsid comprising SEQ ID NO: 1. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2321 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 2. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2321 and a capsid comprising SEQ ID NO: 4534. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2321 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 3. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2321 and a capsid comprising SEQ ID NO: 138. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2321 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 137. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2321 and a capsid comprising SEQ ID NO: 5. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2321 and a capsid encoded by a nucleic acid sequence comprising SEQ ID NO: 6. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2321 and a capsid comprising SEQ ID NO: 4. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2321 and a capsid comprising SEQ ID NO: 11. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2321 and a capsid comprising SEQ ID NO: 2679. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2321 and a capsid comprising SEQ ID NO: 2809. In some embodiments, the AAV particle comprises a viral genome comprising SEQ ID NO: 2321 and a capsid comprising SEQ ID NO: 2871.

II. Formulation and Delivery Pharmaceutical Compositions

According to the present disclosure the AAV particles may be prepared as pharmaceutical compositions. It will be understood that such compositions necessarily comprise one or more active ingredients and, most often, a pharmaceutically acceptable excipient.

Relative amounts of the active ingredient (e.g. AAV particle), a pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition in accordance with the present disclosure may vary, depending upon the identity, size, and/or condition of the subject being treated and further depending upon the route by which the composition is to be administered. For example, the composition may comprise between 0.1% and 99% (w/w) of the active ingredient. By way of example, the composition may comprise between 0.1% and 100%, e.g., between 0.5 and 50%, between 1-30%, between 5-80%, at least 80% (w/w) active ingredient.

In some embodiments, the AAV particle pharmaceutical compositions described herein may comprise at least one payload. As a non-limiting example, the pharmaceutical compositions may contain an AAV particle with 1, 2, 3, 4 or 5 payloads. In some embodiments, the pharmaceutical composition may contain a nucleic acid encoding a payload construct encoding proteins selected from antibodies and/or antibody-based compositions.

Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to any other animal, e.g., to non-human animals, e.g. non-human mammals. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with merely ordinary, if any, experimentation. Subjects to which administration of the pharmaceutical compositions is contemplated include, but are not limited to, humans and/or other primates; mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, dogs, mice, rats, birds, including commercially relevant birds such as poultry, chickens, ducks, geese, and/or turkeys.

In some embodiments, compositions are administered to humans, human patients, or subjects.

Formulations

The AAV particles can be formulated using one or more excipients to: (1) increase stability; (2) increase cell transfection or transduction; (3) permit the sustained or delayed expression of the payload; (4) alter the biodistribution (e.g., target the viral particle to specific tissues or cell types); (5) increase the translation of encoded protein; (6) alter the release profile of encoded protein; and/or (7) allow for regulatable expression of the payload.

Formulations of the present disclosure can include, without limitation, saline, liposomes, lipid nanoparticles, polymers, peptides, proteins, cells transfected with viral vectors (e.g., for transfer or transplantation into a subject) and combinations thereof.

Formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. As used herein the term “pharmaceutical composition” refers to compositions comprising at least one active ingredient and optionally one or more pharmaceutically acceptable excipients.

In general, such preparatory methods include the step of associating the active ingredient with an excipient and/or one or more other accessory ingredients. As used herein, the phrase “active ingredient” generally refers either to an AAV particle carrying a payload region encoding the polypeptides or to the antibody or antibody-based composition encoded by a viral genome of by an AAV particle as described herein.

A pharmaceutical composition in accordance with the present disclosure may be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. As used herein, a “unit dose” refers to a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

In some embodiments, the AAV particles may be formulated in phosphate buffered saline (PBS), in combination with an ethylene oxide/propylene oxide copolymer (also known as Pluronic or poloxamer).

In some embodiments, the AAV particles may be formulated in PBS with 0.001% Pluronic acid (F-68) (poloxamer 188) at a pH of about 7.0.

In some embodiments, the AAV particles may be formulated in PBS with 0.001% Pluronic acid (F-68) (poloxamer 188) at a pH of about 7.3.

In some embodiments, the AAV particles may be formulated in PBS with 0.001% Pluronic acid (F-68) (poloxamer 188) at a pH of about 7.4.

In some embodiments, the AAV particles may be formulated in a solution comprising sodium chloride, sodium phosphate and an ethylene oxide/propylene oxide copolymer.

In some embodiments, the AAV particles may be formulated in a solution comprising sodium chloride, sodium phosphate dibasic, sodium phosphate monobasic and poloxamer 188/Pluronic acid (F-68).

In some embodiments, the AAV particles may be formulated in a solution comprising about 180 mM sodium chloride, about 10 mM sodium phosphate and about 0.001% poloxamer 188. In some embodiments, this formulation may be at a pH of about 7.3. The concentration of sodium chloride in the final solution may be 150 mM-200 mM. As non-limiting examples, the concentration of sodium chloride in the final solution may be 150 mM, 160 mM, 170 mM, 180 mM, 190 mM or 200 mM. The concentration of sodium phosphate in the final solution may be 1 mM-50 mM. As non-limiting examples, the concentration of sodium phosphate in the final solution may be 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 40 mM, or 50 mM. The concentration of poloxamer 188 (Pluronic acid (F-68)) may be 0.0001%-1%. As non-limiting examples, the concentration of poloxamer 188 (Pluronic acid (F-68)) may be 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, or 1%. The final solution may have a pH of 6.8-7.7. Non-limiting examples for the pH of the final solution include a pH of 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, or 7.7.

In some embodiments, the AAV particles of the invention may be formulated in a solution comprising about 1.05% sodium chloride, about 0.212% sodium phosphate dibasic, heptahydrate, about 0.025% sodium phosphate monobasic, monohydrate, and 0.001% poloxamer 188, at a pH of about 7.4. As a non-limiting example, the concentration of AAV particle in this formulated solution may be about 0.001%. The concentration of sodium chloride in the final solution may be 0.1-2.0%, with non-limiting examples of 0.1%, 0.25%, 0.5%, 0.75%, 0.95%, 0.96%, 0.97%, 0.98%, 0.99%, 1.00%, 1.01%, 1.02%, 1.03%, 1.04%, 1.05%, 1.06%, 1.07%, 1.08%, 1.09%, 1.10%, 1.25%, 1.5%, 1.75%, or 2%. The concentration of sodium phosphate dibasic in the final solution may be 0.100-0.300% with non-limiting examples including 0.100%, 0.125%, 0.150%, 0.175%, 0.200%, 0.210%, 0.211%, 0.212%, 0.213%, 0.214%, 0.215%, 0.225%, 0.250%, 0.275%, 0.300%. The concentration of sodium phosphate monobasic in the final solution may be 0.010-0.050%, with non-limiting examples of 0.010%, 0.015%, 0.020%, 0.021%, 0.022%, 0.023%, 0.024%, 0.025%, 0.026%, 0.027%, 0.028%, 0.029%, 0.030%, 0.035%, 0.040%, 0.045%, or 0.050%. The concentration of poloxamer 188 (Pluronic acid (F-68)) may be 0.0001%-1%. As non-limiting examples, the concentration of poloxamer 188 (Pluronic acid (F-68)) may be 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, or 1%. The final solution may have a pH of 6.8-7.7. Non-limiting examples for the pH of the final solution include a pH of 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, or 7.7.

Relative amounts of the active ingredient (e.g. AAV particle), the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition in accordance with the present disclosure may vary, depending upon the identity, size, and/or condition of the subject being treated and further depending upon the route by which the composition is to be administered. For example, the composition may comprise between 0.1% and 99% (w/w) of the active ingredient. By way of example, the composition may comprise between 0.1% and 100%, e.g., between 0.5 and 50%, between 1-30%, between 5-80%, or at least 80% (w/w) active ingredient.

In some embodiments, the AAV formulations described herein may contain sufficient AAV particles for expression of at least one expressed functional antibody or antibody-based composition. As a non-limiting example, the AAV particles may contain viral genomes encoding 1, 2, 3, 4, or 5 functional antibodies.

According to the present disclosure AAV particles may be formulated for CNS delivery. Agents that cross the brain blood barrier may be used. For example, some cell penetrating peptides that can target molecules to the brain blood barrier endothelium may be used for formulation (e.g., Mathupala, Expert Opin Ther Pat., 2009, 19, 137-140; the content of which is incorporated herein by reference in its entirety).

Excipients and Diluents

In some embodiments, a pharmaceutically acceptable excipient may be at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% pure. In some embodiments, an excipient is approved for use for humans and for veterinary use. In some embodiments, an excipient may be approved by United States Food and Drug Administration. In some embodiments, an excipient may be of pharmaceutical grade. In some embodiments, an excipient may meet the standards of the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), the British Pharmacopoeia, and/or the International Pharmacopoeia.

Excipients, as used herein, include, but are not limited to, any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, and the like, as suited to the particular dosage form desired. Various excipients for formulating pharmaceutical compositions and techniques for preparing the composition are known in the art (see Remington: The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro, Lippincott, Williams & Wilkins, Baltimore, Md., 2006; incorporated herein by reference in its entirety). The use of a conventional excipient medium may be contemplated within the scope of the present disclosure, except insofar as any conventional excipient medium may be incompatible with a substance or its derivatives, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition.

Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and/or combinations thereof.

Inactive Ingredients

In some embodiments, AAV particle formulations may comprise at least one inactive ingredient. As used herein, the term “inactive ingredient” refers to one or more agents that do not contribute to the activity of the active ingredient of the pharmaceutical composition included in formulations. In some embodiments, all, none or some of the inactive ingredients which may be used in the formulations of the present disclosure may be approved by the US Food and Drug Administration (FDA).

Pharmaceutical composition formulations of AAV particles disclosed herein may include cations or anions. In some embodiments, the formulations include metal cations such as, but not limited to, Zn2+, Ca2+, Cu2+, Mn2+, Mg+ and combinations thereof. As a non-limiting example, formulations may include polymers and complexes with a metal cation (See e.g., U.S. Pat. Nos. 6,265,389 and 6,555,525, each of which is herein incorporated by reference in its entirety).

III. Administration and Dosing Administration

The AAV particles of the present disclosure may be administered by any delivery route which results in a therapeutically effective outcome. These include, but are not limited to, enteral (into the intestine), gastroenteral, epidural (into the dura mater), oral (by way of the mouth), transdermal, intracerebral (into the cerebrum), intracerebroventricular (into the cerebral ventricles), epicutaneous (application onto the skin), intradermal (into the skin itself), subcutaneous (under the skin), nasal administration (through the nose), intravenous (into a vein), intravenous bolus, intravenous drip, intra-arterial (into an artery), intramuscular (into a muscle), intracardiac (into the heart), intraosseous infusion (into the bone marrow), intrathecal (into the spinal canal), intraparenchymal (into brain tissue), intraperitoneal (infusion or injection into the peritoneum), intravesical infusion, intravitreal (through the eye), intracavernous injection (into a pathologic cavity) intracavitary (into the base of the penis), intravaginal administration, intrauterine, extra-amniotic administration, transdermal (diffusion through the intact skin for systemic distribution), transmucosal (diffusion through a mucous membrane), transvaginal, insufflation (snorting), sublingual, sublabial, enema, eye drops (onto the conjunctiva), ear drops, auricular (in or by way of the ear), buccal (directed toward the cheek), conjunctival, cutaneous, dental (to a tooth or teeth), electro-osmosis, endocervical, endosinusial, endotracheal, extracorporeal, hemodialysis, infiltration, interstitial, intra-abdominal, intra-amniotic, intra-articular, intrabiliary, intrabronchial, intrabursal, intracartilaginous (within a cartilage), intracaudal (within the cauda equine), intracisternal (within the cisterna magna cerebellomedularis), intracorneal (within the cornea), dental intracoronal, intracoronary (within the coronary arteries), intracorporus cavernosum (within the dilatable spaces of the corporus cavernosa of the penis), intradiscal (within a disc), intraductal (within a duct of a gland), intraduodenal (within the duodenum), intradural (within or beneath the dura), intraepidermal (to the epidermis), intraesophageal (to the esophagus), intragastric (within the stomach), intragingival (within the gingivae), intraileal (within the distal portion of the small intestine), intralesional (within or introduced directly to a localized lesion), intraluminal (within a lumen of a tube), intralymphatic (within the lymph), intramedullary (within the marrow cavity of a bone), intrameningeal (within the meninges), intramyocardial (within the myocardium), intraocular (within the eye), intraovarian (within the ovary), intrapericardial (within the pericardium), intrapleural (within the pleura), intraprostatic (within the prostate gland), intrapulmonary (within the lungs or its bronchi), intrasinal (within the nasal or periorbital sinuses), intraspinal (within the vertebral column), intrasynovial (within the synovial cavity of a joint), intratendinous (within a tendon), intratesticular (within the testicle), intrathecal (within the cerebrospinal fluid at any level of the cerebrospinal axis), intrathoracic (within the thorax), intratubular (within the tubules of an organ), intratumor (within a tumor), intratympanic (within the aurus media), intravascular (within a vessel or vessels), intraventricular (within a ventricle), iontophoresis (by means of electric current where ions of soluble salts migrate into the tissues of the body), irrigation (to bathe or flush open wounds or body cavities), laryngeal (directly upon the larynx), nasogastric (through the nose and into the stomach), occlusive dressing technique (topical route administration which is then covered by a dressing which occludes the area), ophthalmic (to the external eye), oropharyngeal (directly to the mouth and pharynx), parenteral, percutaneous, periarticular, peridural, perineural, periodontal, rectal, respiratory (within the respiratory tract by inhaling orally or nasally for local or systemic effect), retrobulbar (behind the pons or behind the eyeball), soft tissue, subarachnoid, subconjunctival, submucosal, topical, transplacental (through or across the placenta), transtracheal (through the wall of the trachea), transtympanic (across or through the tympanic cavity), ureteral (to the ureter), urethral (to the urethra), vaginal, caudal block, diagnostic, nerve block, biliary perfusion, cardiac perfusion, photopheresis, and spinal.

In some embodiments, compositions may be administered in away which allows them to cross the blood-brain barrier, vascular barrier, or other epithelial barrier. The AAV particles of the present disclosure may be administered in any suitable form, either as a liquid solution or suspension, as a solid form suitable for liquid solution or suspension in a liquid solution. The AAV particles may be formulated with any appropriate and pharmaceutically acceptable excipient.

In some embodiments, the AAV particles of the present disclosure may be delivered to a subject via a single route administration.

In some embodiments, the AAV particles of the present disclosure may be delivered to a subject via a multi-site route of administration. A subject may be administered at 2, 3, 4, 5, or more than 5 sites.

In some embodiments, a subject may be administered the AAV particles of the present disclosure using a bolus infusion.

In some embodiments, a subject may be administered the AAV particles of the present disclosure using sustained delivery over a period of minutes, hours, or days. The infusion rate may be changed depending on the subject, distribution, formulation or another delivery parameter.

In some embodiments, the AAV particles may be delivered by more than one route of administration. As non-limiting examples of combination administrations, AAV particles may be delivered by intrathecal and intracerebroventricular, or by intravenous and intraparenchymal administration.

Intravenous Administration

In some embodiments, the AAV particles may be administered to a subject by systemic administration.

In some embodiments, the systemic administration is intravenous administration.

In another embodiment, the systemic administration is intraarterial administration.

In some embodiments, the AAV particles of the present disclosure may be administered to a subject by intravenous administration.

In some embodiments, the intravenous administration may be achieved by subcutaneous delivery.

In some embodiments, the intravenous administration may be achieved by a tail vein injection (e.g., in a mouse model).

In some embodiments, the intravenous administration may be achieved by retro-orbital injection.

Administration to the CNS

In some embodiments, the AAV particles may be delivered by direct injection into the brain. As a non-limiting example, the brain delivery may be by intrahippocampal administration.

In some embodiments, the AAV particles of the present disclosure may be administered to a subject by intraparenchymal administration. In some embodiments, the intraparenchymal administration is to tissue of the central nervous system.

In some embodiments, the AAV particles of the present disclosure may be administered to a subject by intracranial delivery (See. e.g., U.S. Pat. No. 8,119,611; the content of which is incorporated herein by reference in its entirety).

In some embodiments, the AAV particles may be delivered by injection into the CSF pathway. Non-limiting examples of delivery to the CSF pathway include intrathecal and intracerebroventricular administration.

In some embodiments, the AAV particles may be delivered to the brain by systemic delivery. As a non-limiting example, the systemic delivery may be by intravascular administration. As a non-limiting example, the systemic or intravascular administration may be intravenous.

In some embodiments, the AAV particles of the present disclosure may be delivered by intraocular delivery route. A non-limiting example of intraocular administration include an intravitreal injection.

Intramuscular Administration

In some embodiments, the AAV particles may be delivered by intramuscular administration. Whilst not wishing to be bound by theory, the multi-nucleated nature of muscle cells provides an advantage to gene transduction subsequent to AAV delivery. Cells of the muscle are capable of expressing recombinant proteins with the appropriate post-translational modifications. The enrichment of muscle tissue with vascular structures allows for transfer to the blood stream and whole-body delivery. Examples of intramuscular administration include systemic (e.g., intravenous), subcutaneous or directly into the muscle. In some embodiments, more than one injection is administered.

In some embodiments, the AAV particles of the present disclosure may be delivered by intramuscular delivery route. (See, e.g., U.S. Pat. No. 6,506,379: the content of which is incorporated herein by reference in its entirety). Non-limiting examples of intramuscular administration include an intravenous injection or a subcutaneous injection.

In some embodiments, the AAV particles of the present disclosure are administered to a subject and transduce muscle of a subject. As a non-limiting example, the AAV particles are administered by intramuscular administration.

In some embodiments, the AAV particles of the present disclosure may be administered to a subject by subcutaneous administration.

In some embodiments, the intramuscular administration is via systemic delivery.

In some embodiments, the intramuscular administration is via intravenous delivery.

In some embodiments, the intramuscular administration is via direct injection to the muscle.

In some embodiments, the muscle is transduced by administration, and this is referred to as intramuscular administration.

In some embodiments, the intramuscular delivery comprises administration at one site.

In some embodiments, the intramuscular delivery comprises administration at more than one site. In some embodiments, the intramuscular delivery comprises administration at two sites. In some embodiments, the intramuscular delivery comprises administration at three sites. In some embodiments, the intramuscular delivery comprises administration at four sites. In some embodiments, the intramuscular delivery comprises administration at more than four sites.

In some embodiments, intramuscular delivery is combined with at least one other method of administration.

In some embodiments, the AAV particles that may be administered to a subject by peripheral injections. Non-limiting examples of peripheral injections include intraperitoneal, intramuscular, intravenous, conjunctival, or joint injection. It was disclosed in the art that the peripheral administration of AAV vectors can be transported to the central nervous system, for example, to the motor neurons (e.g., U.S. Patent Publication Nos. US20100240739 and US20100130594; the content of each of which is incorporated herein by reference in their entirety).

In some embodiments, the AAV particles of the present disclosure may be administered to a subject by intraparenchymal administration. In some embodiments, the intraparenchymal administration is to muscle tissue.

In some embodiments, the AAV particles of the present disclosure are delivered as described in Bright et al 2015 (Neurobiol Aging. 36(2):693-709), the contents of which are herein incorporated by reference in their entirety.

In some embodiments, the AAV particles of the present disclosure are administered to the gastrocnemius muscle of a subject.

In some embodiments, the AAV particles of the present disclosure are administered to the bicep femorii of the subject.

In some embodiments, the AAV particles of the present disclosure are administered to the tibialis anterior muscles.

In some embodiments, the AAV particles of the present disclosure are administered to the soleus muscle.

Depot Administration

As described herein, in some embodiments, pharmaceutical compositions, AAV particles of the present disclosure are formulated in depots for extended release. Generally, specific organs or tissues (“target tissues”) are targeted for administration.

In some aspects, pharmaceutical compositions, AAV particles of the present disclosure are spatially retained within or proximal to target tissues. Provided are methods of providing pharmaceutical compositions, AAV particles, to target tissues of mammalian subjects by contacting target tissues (which comprise one or more target cells) with pharmaceutical compositions, AAV particles, under conditions such that they are substantially retained in target tissues, meaning that at least 10, 20, 30, 40, 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, 99.9, 99.99 or greater than 99.99% of the composition is retained in the target tissues. Advantageously, retention is determined by measuring the amount of pharmaceutical compositions, AAV particles, that enter one or more target cells. For example, at least 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%, or greater than 99.99% of pharmaceutical compositions, AAV particles, administered to subjects are present intracellularly at a period of time following administration. For example, intramuscular injection to mammalian subjects may be performed using aqueous compositions comprising pharmaceutical compositions, AAV particles of the present disclosure and one or more transfection reagents, and retention is determined by measuring the amount of pharmaceutical compositions, AAV particles, present in muscle cells.

Certain aspects are directed to methods of providing pharmaceutical compositions, AAV particles of the present disclosure to a target tissues of mammalian subjects, by contacting target tissues (comprising one or more target cells) with pharmaceutical compositions, AAV particles under conditions such that they are substantially retained in such target tissues. Pharmaceutical compositions, AAV particles comprise enough active ingredient such that the effect of interest is produced in at least one target cell. In some embodiments, pharmaceutical compositions, AAV particles generally comprise one or more cell penetration agents, although “naked” formulations (such as without cell penetration agents or other agents) are also contemplated, with or without pharmaceutically acceptable carriers.

Delivery

In some embodiments, the AAV particles or pharmaceutical compositions of the present disclosure may be administered or delivered using the methods for treatment of disease described in U.S. Pat. No. 8,999,948, or International Publication No. WO2014178863, the contents of which are herein incorporated by reference in their entirety.

In some embodiments, the AAV particles or pharmaceutical compositions of the present disclosure may be administered or delivered using the methods for delivering gene therapy in Alzheimer's Disease or other neurodegenerative conditions as described in US Application No. 20150126590, the contents of which are herein incorporated by reference in their entirety.

In some embodiments, the AAV particles or pharmaceutical compositions of the present disclosure may be administered or delivered using the methods for delivery of a CNS gene therapy as described in U.S. Pat. Nos. 6,436,708, and 8,946,152, and International Publication No. WO2015168666, the contents of which are herein incorporated by reference in their entirety.

In some embodiments, the AAV particle or pharmaceutical compositions of the present disclosure may be administered or delivered using the methods for delivering proteins using AAV vectors described in European Patent Application No. EP2678433, the contents of which are herein incorporated by reference in their entirety.

In some embodiments, the AAV particle or pharmaceutical compositions of the present disclosure may be administered or delivered using the methods for delivering DNA to the bloodstream described in U.S. Pat. No. 6,211,163, the contents of which are herein incorporated by reference in their entirety.

In some embodiments, the AAV particle or pharmaceutical compositions of the present disclosure may be administered or delivered using the methods for delivering a payload to the central nervous system described in U.S. Pat. No. 7,588,757, the contents of which are herein incorporated by reference in their entirety.

In some embodiments, the AAV particle or pharmaceutical compositions of the present disclosure may be administered or delivered using the methods for delivering a payload described in U.S. Pat. No. 8,283,151, the contents of which are herein incorporated by reference in their entirety.

In some embodiments, the AAV particle or pharmaceutical compositions of the present disclosure may be administered or delivered using the methods for delivering a payload using a glutamic acid decarboxylase (GAD) delivery vector described in International Patent Publication No. WO2001089583, the contents of which are herein incorporated by reference in their entirety.

In some embodiments, the AAV particle or pharmaceutical compositions of the present disclosure may be administered or delivered using the methods for delivering a payload to neural cells described in International Patent Publication No. WO2012057363, the contents of which are herein incorporated by reference in their entirety.

Delivery to Cells

The present disclosure provides a method of delivering to a cell or tissue any of the above-described AAV particles, comprising contacting the cell or tissue with said AAV particle or contacting the cell or tissue with a formulation comprising said AAV particle, or contacting the cell or tissue with any of the described compositions, including pharmaceutical compositions. The method of delivering the AAV particle to a cell or tissue can be accomplished in vitro, ex vivo, or in vivo.

Delivery to Subjects

The present disclosure additionally provides a method of delivering to a subject, including a mammalian subject, any of the above-described AAV particles comprising administering to the subject said AAV particle, or administering to the subject a formulation comprising said AAV particle, or administering to the subject any of the described compositions, including pharmaceutical compositions.

Dose and Regimen

The present disclosure provides methods of administering AAV particles in accordance with the disclosure to a subject in need thereof. The pharmaceutical, diagnostic, or prophylactic AAV particles and compositions of the present disclosure may be administered to a subject using any amount and any route of administration effective for preventing, treating, managing, or diagnosing diseases, disorders and/or conditions. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular composition, its mode of administration, its mode of activity, and the like. The subject may be a human, a mammal, or an animal. Compositions in accordance with the disclosure are typically formulated in unit dosage form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present disclosure may be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective, prophylactically effective, or appropriate diagnostic dose level for any particular individual will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific payload employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific AAV particle employed; the duration of the treatment; drugs used in combination or coincidental with the specific AAV particle employed; and like factors well known in the medical arts.

In certain embodiments, AAV particle pharmaceutical compositions in accordance with the present disclosure may be administered at dosage levels sufficient to deliver from about 0.0001 mg/kg to about 100 mg/kg, from about 0.001 mg/kg to about 0.05 mg/kg, from about 0.005 mg/kg to about 0.05 mg/kg, from about 0.001 mg/kg to about 0.005 mg/kg, from about 0.05 mg/kg to about 0.5 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, or from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic, diagnostic, or prophylactic, effect. It will be understood that the above dosing concentrations may be converted to vg or viral genomes per kg or into total viral genomes administered by one of skill in the art.

In certain embodiments, AAV particle pharmaceutical compositions in accordance with the present disclosure may be administered at about 10 to about 600 μl/site, 50 to about 500 μl/site, 100 to about 400 μl/site, 120 to about 300 μl/site, 140 to about 200 μl/site, about 160 μl/site. As non-limiting examples, AAV particles may be administered at 50 μl/site and/or 150 μl/site.

In certain embodiments, the desired dosage may be delivered using multiple administrations (e.g., two, three, four, or more than four administrations). When multiple administrations are employed, split dosing regimens such as those described herein may be used. As used herein, a “split dose” is the division of “single unit dose” or total daily dose into two or more doses, e.g., two or more administrations of the “single unit dose”. As used herein, a “single unit dose” is a dose of any therapeutic administered in one dose/at one time/single route/single point of contact, i.e., single administration event.

The desired dosage of the AAV particles of the present disclosure may be administered as a “pulse dose” or as a “continuous flow”. As used herein, a “pulse dose” is a series of single unit doses of any therapeutic administered with a set frequency over a period of time. As used herein, a “continuous flow” is a dose of therapeutic administered continuously for a period of time in a single route/single point of contact, i.e., continuous administration event. A total daily dose, an amount given or prescribed in 24-hour period, may be administered by any of these methods, or as a combination of these methods, or by any other methods suitable for a pharmaceutical administration.

In some embodiments, delivery of the AAV particles of the present disclosure to a subject provides neutralizing activity to a subject. The neutralizing activity can be for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 10 months, 1 year, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 20 months, 21 months, 22 months, 23 months, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years or more than 10 years.

In some embodiments, delivery of the AAV particles of the present disclosure results in minimal serious adverse events (SAEs) as a result of the delivery of the AAV particles.

In some embodiments, delivery of AAV particles may comprise a total dose between about 1×10⁶VG and about 1×10¹⁶VG. In some embodiments, delivery may comprise a total dose of about 1×10⁶, 2×10⁶, 3×10⁶, 4×10⁶, 5×10⁶, 6×10⁶, 7×10⁶, 8×10⁶, 9×10⁶, 1×10⁷, 2×10⁷, 3×10⁷, 4×10⁷, 5×10⁷, 6×10⁷, 7×10⁷, 8×10⁷, 9×10⁷, 1×10⁸, 2×10⁸, 3×10⁸, 4×10⁸, 5×10⁸, 6×10⁸, 7×10⁸, 8×10⁸, 9×10⁸, 1×10⁹, 2×10⁹, 3×10⁹, 4×10⁹, 5×10⁹, 6×10⁹, 7×10⁹, 8×10⁹, 9×10⁹, 1×10¹⁰, 1.9×10¹⁰, 2×10¹⁰, 3×10¹⁰, 3.73×10¹⁰, 4×10¹⁰, 5×10¹⁰, 6×10¹⁰, 7×10¹⁰, 8×10¹⁰, 9×10¹⁰, 1×10¹¹, 2×10¹¹, 2.5×10¹¹, 3×10¹¹, 4×10¹¹, 5×10¹¹, 6×10¹¹, 7×10¹¹, 8×10¹¹, 9×10¹¹, 1×10¹², 2×10¹², 3×10¹², 4×10¹², 5×10¹², 6×10¹², 7×10¹², 8×10¹², 9×10¹², 1×10¹³, 2×10¹³, 3×10¹³, 4×10¹³, 5×10¹³, 6×10¹³, 7×10¹³, 8×10¹³, 9×10¹³, 1×10¹⁴, 2×10¹⁴, 3×10¹⁴, 4×10¹⁴, 5×10¹⁴, 6×10¹⁴, 7×10¹⁴, 8×10¹⁴, 9×10¹⁴, 1×10¹⁵, 2×10, 3×10¹⁵, 4×10¹⁵, 5×10¹⁵, 6×10¹⁵, 7×10¹⁵, 8×10¹⁵, 9×10¹⁵, or 1×10¹⁶ VG. As a non-limiting example, the total dose is 1×10¹³VG. As another non-limiting example, the total dose is 2.1×10¹² VG.

In some embodiments, delivery of AAV particles may comprise a composition concentration between about 1×10⁶ VG/mL and about 1×10¹⁶ VG/mL. In some embodiments, delivery may comprise a composition concentration of about 1×10⁶, 2×10⁶, 3×10⁶, 4×10⁶, 5×10⁶, 6×10⁶, 7×10⁶, 8×10⁶, 9×10⁶, 1×10⁷, 2×10⁷, 3×10⁷, 4×10⁷, 5×10⁷, 6×10⁷, 7×10⁷, 8×10⁷, 9×10⁷, 1×10⁸, 2×10⁸, 3×10⁸, 4×10⁸, 5×10⁸, 6×10⁸, 7×10⁸, 8×10⁸, 9×10⁸, 1×10⁹, 2×10⁹, 3×10⁹, 4×10⁹, 5×10⁹, 6×10⁹, 7×10⁹, 8×10⁹, 9×10⁹, 1×10¹⁰, 2×10¹⁰, 3×10¹⁰, 4×10¹⁰, 5×10¹⁰, 6×10¹⁰, 7×10¹⁰, 8×10¹⁰, 9×10¹⁰, 1×10¹¹, 2×10¹¹, 3×10¹¹, 4×10¹¹, 5×10¹¹, 6×10¹¹, 7×10¹¹, 8×10¹¹, 9×10¹¹, 1×10¹², 2×10¹², 3×10¹², 4×10¹², 5×10¹², 6×10¹², 7×10¹², 8×10¹², 9×10¹², 1×10¹³, 2×10¹³, 3×10¹³, 4×10¹³, 5×10¹³, 6×10¹³, 7×10¹³, 8×10¹³, 9×10¹³, 1×10¹⁴, 2×10¹⁴, 3×10¹⁴, 4×10¹⁴, 5×10¹⁴, 6×10¹⁴, 7×10¹⁴, 8×10¹⁴, 9×10¹⁴, 1×10¹⁵, 2×10, 3×10¹⁵, 4×10¹⁵, 5×10¹⁵, 6×10¹⁵, 7×10¹⁵, 8×10¹⁵, 9×10¹⁵, or 1×10¹⁶ VG/mL. In some embodiments, the delivery comprises a composition concentration of 1×10¹³ VG/mL. In some embodiments, the delivery comprises a composition concentration of 2.1×10¹² VG/mL.

Combinations

The AAV particles may be used in combination with one or more other therapeutic, prophylactic, research or diagnostic agents. By “in combination with,” it is not intended to imply that the agents must be administered at the same time and/or formulated for delivery together, although these methods of delivery are within the scope of the present disclosure. Compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. In general, each agent will be administered at a dose and/or on a time schedule determined for that agent. In some embodiments, the present disclosure encompasses the delivery of pharmaceutical, prophylactic, research, or diagnostic compositions in combination with agents that may improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body.

Measurement of Expression

Expression of payloads from viral genomes may be determined using various methods known in the art such as, but not limited to immunochemistry (e.g., IHC), in situ hybridization (ISH), enzyme-linked immunosorbent assay (ELISA), affinity ELISA, ELISPOT, flow cytometry, immunocytology, immunohistochemistry, surface plasmon resonance analysis, kinetic exclusion assay, liquid chromatography-mass spectrometry (LCMS), high-performance liquid chromatography (HPLC), BCA assay, immunoelectrophoresis, Western blot, SDS-PAGE, protein immunoprecipitation, and/or PCR.

In some embodiments, the ELISA assays used are those described in Liu et al 2016, the contents of which are herein incorporated by reference in their entirety (Liu, W et al., 2016 J Neurosci 36(49):12425-12435).

IV. Methods and Uses of the Compositions

The present disclosure provides a method for treating a disease, disorder and/or condition in a mammalian subject, including a human subject, comprising administering to the subject any of the AAV particles described herein or administering to the subject any of the described compositions, including pharmaceutical compositions, described herein.

In some embodiments, the AAV particles of the present disclosure are administered to a subject prophylactically.

In some embodiments, the AAV particles of the present disclosure are administered to a subject having at least one of the diseases described herein.

In some embodiments, the AAV particles of the present disclosure are administered to a subject to treat a disease or disorder described herein. The subject may have the disease or disorder or may be at-risk to developing the disease or disorder.

In some embodiments, the AAV particles of the present disclosure are part of an active immunization strategy to protect against diseases and disorders. In an active immunization strategy, a vaccine or AAV particles are administered to a subject to prevent an infectious disease by activating the subject's production of antibodies that can fight off invading bacteria or viruses.

In some embodiments, the AAV particles of the present disclosure are part of a passive immunization strategy. In a passive immunization strategy, antibodies against a particular infectious agent are given directly to the subject.

In some embodiments, the AAV particles of the present disclosure may be used for passive immunotherapy of tauopathy, (e.g. Alzheimer Disease or Frontotemporal Dementia), as described in Liu et al, the contents of which are herein incorporated by reference in their entirety (Liu, W et al., 2016 J Neurosci 36(49):12425-12435). As a non-limiting example, the AAV particles of the present disclosure may encode a PHF1 antibody. Heavy and light chains of the PHF1 antibody may be linked by a Tav2A and/or Furin 2A linker sequence. Antibody expression may be under the control of a CAG promoter. The AAV particle may comprise, as a non-limiting example, an AAVrh.10 serotype capsid. Further, these PHF1 encoding AAV particles may be administered by bilateral intraparenchymal delivery directly to the hippocampus. Such treatment with AAV-PHF1 may result in a 50-fold increase in antibody levels in the hippocampus as compared to antibody levels subsequent to systemic administration. Neuropathological tau species in the hippocampus may be reduced as much as 80-90% and hippocampal atrophy may be fully rescued after treatment with AAV particles of the present disclosure.

In some embodiments, the AAV particles of the present disclosure may be used to treat tauopathy as described in Ising et al, the contents of which are herein incorporated by reference in their entirety (Ising, C et al., 2017 J Exp Med April 17, Epub ahead of print). As a non-limiting example, the AAV particles of the present disclosure may encode an HJ8.5, HJ8.7, or Tau5 antibody or a single chain variable fragment (scFv) derived therefrom. Heavy and light chains of the HJ8.5 antibody or scFv may be linked by variable length linker sequences and may be flexible glycine and/or serine linkers. The AAV particle may comprise, as a non-limiting example, an AAV2/8 serotype. Further, these HJ8.5, HJ8.7 or Tau5 encoding AAV particles may be administered by bilateral intracerebroventricular delivery. Such treatment with HJ8.5, HJ8.7 or Tau5 encoding AAV particles may result in a significant reduction in neuropathological tau species in the hippocampus.

Passive immunization by intravenous (or intraperitoneal in mice) delivery of antibody has been shown to result in substantial serum levels of antibody (Chai et al., 2011, J Biol Chem., 286, 34457-34467, the contents of which are herein incorporated by reference in their entirety) and reduced tau pathology in mouse models of tauopathy (e.g., P301L or P301S mice). However, these reductions in tau pathology are considered modest (e.g., about 34%) and require high and repeated dosing to achieve. Passive immunization strategies are thought to be limited in their ability to deliver large quantity of antibody to the brain, which may limit efficacy, and are also challenged in addressing intracellular aggregates. In some embodiments, delivery of an AAV particle comprising a viral genome encoding an anti-tau antibody can be used to overcome the limitations seen with passive immunization strategies.

In some embodiments, the administration of AAV particles of the present disclosure may result in substantially higher antibody levels in the target tissue (e.g., CNS) of the subject than if anti-tau antibodies were administered by passive immunization. In some embodiments, AAV mediated delivery can result in 1.5-16 fold higher antibody levels in the brain than if delivered by passive immunization. Whilst not wishing to be bound by theory, passive immunization is thought to generate 20-40 ng of antibody per mg of protein in the brain of the subject. In some embodiments, AAV-mediated delivery results in antibody levels 2-5× above the levels seen with passive immunization. In some embodiments, AAV-mediated delivery results in antibody levels 1.5-3× above the levels seen with passive immunization. In some embodiments, AAV-mediated delivery results in antibody levels 5-10× above the levels seen with passive immunization. In some embodiments, AAV-mediated delivery results in antibody levels 8-16× above the levels seen with passive immunization.

Diagnostic Applications

The AAV particles of the present disclosure may be used for diagnostic purposes or as diagnostic tools for any disease or disorder. As non-limiting examples, the AAV particles of the present disclosure or the antibodies encoded within the viral genome therein may be used as a biomarker for disease diagnosis. As a second non-limiting example, the AAV particles of the present disclosure or the antibodies encoded within the viral genome therein may be used for diagnostic imaging purposes, e.g., MRI, PET, CT or ultrasound.

Preventative Applications

The AAV particles of the present disclosure or the antibodies encoded by the viral genome therein may be used to prevent disease or stabilize the progression of disease. In some embodiments, the AAV particles of the present disclosure are used to as a prophylactic to prevent a disease or disorder in the future. In some embodiments, the AAV particles of the present disclosure are used to halt further progression of a disease or disorder. As a non-limiting example, the AAV particles may be used in a manner similar to that of a vaccine.

Research Applications

The AAV particles of the present disclosure or the antibodies encoded by the viral genome therein may also be used as research tools. The AAV particles may be used as in any research experiment, e.g., in vivo or in vitro experiments. In a non-limiting example, the AAV particles may be used in cultured cells. The cultured cells may be derived from any origin known to one with skill in the art, and may be as non-limiting examples, derived from a stable cell line, an animal model or a human patient or control subject. In a non-limiting example, the AAV particles may be used in in vivo experiments in animal models (i.e., mouse, rat, rabbit, dog, cat, non-human primate, guinea pig, ferret, c-elegans, drosophila, zebrafish, or any other animal used for research purposes, known in the art). In another non-limiting example, the AAV particles may be used in human research experiments or human clinical trials.

Combination Applications

The AAV particles may be used as a combination therapy with any other therapeutic molecule known in the art. The therapeutic molecule may be approved by the US Food and Drug Administration or may be in clinical trial or at the preclinical research stage. The therapeutic molecule may utilize any therapeutic modality known in the art, with non-limiting examples including gene silencing or interference (i.e., miRNA, siRNA, RNAi, shRNA), gene editing (i.e., TALEN, CRISPR/Cas9 systems, zinc finger nucleases), and gene, protein or enzyme replacement.

Therapeutic Applications

The present disclosure additionally provides a method for treating neurological diseases and/or disorders in a mammalian subject, including a human subject, comprising administering to the subject any of the AAV particles. In some cases, neurological diseases and/or disorders treated according to methods described herein include indications involving irregular expression or aggregation of tau. Such indications may include, but are not limited to Alzheimer's disease (AD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Frontotemporal lobar degeneration (FTLD), Frontotemporal dementia (FTD), chronic traumatic encephalopathy (CTE), Progressive Supranuclear Palsy (PSP), Down's syndrome, Pick's disease, Corticobasal degeneration (CBD), Corticobasal syndrome, Amyotrophic lateral sclerosis (ALS), Prion diseases, Creutzfeldt-Jakob disease (CJD), Multiple system atrophy, Tangle-only dementia, and Progressive subcortical gliosis.

In some embodiments, methods of treating neurological diseases and/or disorders in a subject in need thereof may comprise the steps of: (1) deriving, generating and/or selecting an anti-tau antibody, antibody-based composition or fragment thereof: (2) producing an AAV particle with a viral genome that includes a payload region encoding the selected antibody of (1); and (3) administering the AAV particle (or pharmaceutical composition thereof) to the subject.

The present disclosure provides a method for administering to a subject in need thereof, including a human subject, a therapeutically effective amount of the AAV particles to slow, stop or reverse disease progression. As a non-limiting example, disease progression may be measured by cognitive tests such as, but not limited to, the Mini-Mental State Exam (MMSE) or other similar diagnostic tool(s), known to those skilled in the art. As another non-limiting example, disease progression may be measured by change in the pathological features of the brain. CSF or other tissues of the subject, such as, but not limited to a decrease in levels of tau (either soluble or insoluble). In some embodiments levels of insoluble hyperphosphorylated tau are decreased. In some embodiments levels of soluble tau are decreased. In some embodiments both soluble and insoluble tau are decreased. In some embodiments, levels of insoluble hyperphosphorylated tau are increased. In some embodiments levels of soluble tau are increased. In some embodiments both insoluble and soluble tau levels are increased. In some embodiments, neurofibrillary tangles are decreased in size, number, density, or combination thereof. In another embodiment, neurofibrillary tangles are increased in size, number, density or combination thereof.

Alzheimer's Disease

Alzheimer Disease (AD) is a debilitating neurodegenerative disease currently afflicting more than 35 million people worldwide, with that number expected to double in coming decades. Symptomatic treatments have been available for many years but these treatments do not address the underlying pathophysiology. Recent clinical trials using these and other treatments have largely failed and, to date, no known cure has been identified.

The AD brain is characterized by the presence of two forms of pathological aggregates, the extracellular plaques composed of β-amyloid (Aβ) and the intracellular neurofibrillary tangles (NFT) comprised of hyperphosphorylated microtubule associated protein tau. Based on early genetic findings, β-amyloid alterations were thought to initiate disease, with changes in tau considered downstream. Thus, most clinical trials have been Aβ-centric. Although no mutations of the tau gene have been linked to AD, such alterations have been shown to result in a family of dementias known as tauopathies, demonstrating that changes in tau can contribute to neurodegenerative processes. Tau is normally a very soluble protein known to associate with microtubules based on the extent of its phosphorylation. Hyperphosphorylation of tau depresses its binding to microtubules and microtubule assembly activity. In tauopathies, the tau becomes hyperphosphorylated, misfolds and aggregates as NFT of paired helical filaments (PHF), twisted ribbons or straight filaments. In AD, NFT pathology, rather than plaque pathology, correlates more closely with neuropathological markers such as neuronal loss, synaptic deficits, severity of disease and cognitive decline. NFT pathology marches through the brain in a stereotyped manner and animal studies suggest a trans-cellular propagation mechanism along neuronal connections.

Several approaches have been proposed for therapeutically interfering with progression of tau pathology and preventing the subsequent molecular and cellular consequences. Given that NFT are composed of a hyperphosphorylated, misfolded and aggregated form of tau, interference at each of these stages has yielded the most avidly pursued set of targets. Introducing agents that limit phosphorylation, block misfolding or prevent aggregation have all generated promising results. Passive and active immunization with late stage anti-phospho-tau antibodies in mouse models have led to dramatic decreases in tau aggregation and improvements in cognitive parameters. It has also been suggested that introduction of anti-tau antibodies can prevent the trans-neuronal spread of tau pathology.

The vectored antibody delivery (VAD) of tau disease associated antibodies of the present disclosure may be used to treat subjects suffering from AD and other tauopathies. In some cases, methods of the present disclosure may be used to treat subjects suspected of developing AD or other tauopathies.

Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17 (FTDP-17)

Although Alzheimer's disease is, in part, characterized by the presence of tau pathology, no known mutations in the tau gene have been causally linked to the disease. Mutations in the tau gene have been shown to lead to an autosomal dominantly inherited tauopathy known as frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and demonstrate that alterations in tau can lead to neurodegenerative changes in the brain. Mutations in the tau gene that lead to FTDP-17 are thought to influence splicing patterns, thereby leading to an elevated proportion of tau with four microtubule binding domains (rather than three). These molecules are considered to be more amyloidogenic, meaning they are more likely to become hyperphosphorylated and more likely to aggregate into NFT (Hutton, M. et al., 1998, Nature 393(6686):702-5). Although physically and behaviorally, FTDP-17 patients can appear quite similar to Alzheimer's disease patients, at autopsy FTDP-17 brains lack the prominent Aβ plaque pathology of an AD brain (Gotz, J. et al., 2012, British Journal of Pharmacology 165(5):1246-59). Therapeutically targeting the aggregates of tau protein may ameliorate and prevent degenerative changes in the brain and potentially lead to improved cognitive ability.

As of today, there is no treatment to prevent, slow the progression, or cure FTDP-17. Medication may be prescribed to reduce aggressive, agitated or dangerous behavior. There remains a need for therapy affecting the underlying pathophysiology, such as antibody therapies targeting tau protein.

In some embodiments, the vectored antibody delivery of the present disclosure may be used to treat subjects suffering from FTDP-17. In some cases, methods of the present disclosure may be used to treat subjects suspected of developing FTDP-17.

Chronic Traumatic Encephalopathy

Unlike the genetically linked tauopathies, chronic traumatic encephalopathy is a degenerative tauopathy linked to repeated head injuries. The disease was first described in boxers who behaved “punch drunk” and has since been identified primarily in athletes that play American football, ice hockey, wrestling and other contact sports. The brains of those suffering from CTE are characterized by distinctive patterns of brain atrophy accompanied by accumulation of hyperphosphorylated species of aggregated tau in NFT. In CTE, pathological changes in tau are accompanied by a number of other pathobiological processes, such as inflammation (Daneshvar, D. H. et al., 2015 Mol Cell Neurosci 66(Pt B): 81-90). Targeting the tau aggregates may provide reprieve from the progression of the disease and may allow cognitive improvement.

As of today, there is no medical therapy to treat or cure CTE. The condition is only diagnosed after death, due to lack of in vivo techniques to identify CTE specific biomarkers. There remains a need for therapy affecting the underlying pathophysiology, such as antibody therapies targeting tau protein.

In some embodiments, the vectored antibody delivery methods of the present disclosure may be used to treat subjects suffering from CTE. In some cases, methods of the present disclosure may be used to treat subjects suspected of developing CTE.

Prion Diseases

Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are a group of rare progressive conditions affecting the nervous system. The related conditions are rare and are typically caused by mutations in the PRNP gene which enables production of the prion protein. Gene mutations lead to an abnormally structured prion protein. Alternatively, the abnormal prion may be acquired by exposure from an outside source, e.g. by consumption of beef products containing the abnormal prion protein. Abnormal prions are misfolded, causing the brain tissue to degenerate rapidly. Prion diseases include, but are not limited to, Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal insomnia (FFI), variably protease-sensitive prionopathy (VPSPr), and kuru. Prion diseases are rare. Approximately 350 cases of prion diseases are diagnosed in the US annually.

CJD is a degenerative brain disorder characterized by problems with muscular coordination, personality changes including mental impairment, impaired vision, involuntary muscle jerks, weakness and eventually coma. The most common categories of CJD are sporadic, hereditary due to a genetic mutation, and acquired. Sporadic CJD is the most common form affecting people with no known risk factors for the disease. The acquired form of CJD is transmitted by exposure of the brain and nervous system tissue to the prion. As an example, variant CJD (vCDJ) is linked to a bovine spongiform encephalopathy (BSE), also known as a ‘mad cow’ disease. CJD is fatal and patients typically die within one year of diagnosis.

Prion diseases are associated with an infectious agent consisting of an alternative conformational isoform of the prion protein, PrPSc. PrPSc replication is considered to occur through an induction of the infectious prion in the normal prion protein (PrPC). The replication occurs without a nucleic acid.

As of today, there is no therapy to manage or cure CJD, or other prion diseases. Typically, treatment is aimed at alleviating symptoms and increasing comfortability of the patient, e.g. with pain relievers. There remains a need for therapy affecting the underlying pathophysiology, such as antibody therapies targeting the prion protein.

In some embodiments, vectored antibody delivery methods of the present disclosure may be used to treat subjects suffering from a prion disease. In some cases, methods of the present disclosure may be used to treat subjects suspected of developing a prion disease.

Neurodegeneration and Stroke

Neurodegenerative diseases and other diseases of the nervous system share many common features. Neurodegenerative diseases, in particular, are a group of conditions characterized by progressive loss of neuronal structure and function, ultimately leading to neuronal cell death. Neurons are the building blocks of the nervous system(s) and are generally not able to reproduce and/or be replaced, and therefore neuron damage and/or death is especially devastating. Other, non-degenerating diseases that lead to neuronal cell loss, such as stroke, have similarly debilitating outcomes. Targeting molecules that contribute to the deteriorating cell structure or function may prove beneficial generally for treatment of nervous system diseases, neurodegenerative disease and/or stroke.

Certain molecules are believed to have inhibitory effects on neurite outgrowth, contributing to the limited ability of the central nervous system to repair. Such molecules include, but are not limited to, myelin associated proteins, such as, but not limited to, RGM (Repulsive guidance molecule), NOGO (Neurite outgrowth inhibitor), NOGO receptor, MAG (myelin associated glycoprotein), and MAI (myelin associated inhibitor). In some embodiments, the vectored antibody delivery of the present disclosure is utilized to target the aforementioned antigens (e.g., neurite outgrowth inhibitors).

Many neurodegenerative diseases are associated with aggregation of misfolded proteins, including, but not limited to, alpha synuclein, tau, amyloid β, prion proteins, TDP-43, and huntingtin (see, e.g. De Genst et al., 2014, Biochim Biophys Acta; 1844(11):1907-1919, and Yu et al., 2013, Neurotherapeutics.; 10(3): 459-472, references therein). The aggregation results from disease-specific conversion of soluble proteins to an insoluble, highly ordered fibrillary deposit. This conversion is thought to prevent the proper disposal or degradation of the misfolded protein, thereby leading to further aggregation. Conditions associated with alpha synuclein and tau may be referred to as “synucleinopathies” and “tauopathies”, respectively. In some embodiments, the vectored antibody delivery of the present disclosure is utilized to target the aforementioned antigens (e.g., misfolded or aggregated proteins).

AAV Particles and methods of using the AAV particles described in the present disclosure may be used to prevent, manage and/or treat tauopathies or tau associated disease. As a non-limiting example, the AAV particles of the present disclosure comprise a nucleic acid sequence encoding at least one of the sequences described in Table 3.

V. Kits and Devices Kits

In some embodiments, the disclosure provides a variety of kits for conveniently and/or effectively carrying out methods of the present disclosure. Typically, kits will comprise sufficient amounts and/or numbers of components to allow a user to perform multiple treatments of a subject(s) and/or to perform multiple experiments.

Any of the AAV particles of the present disclosure may be comprised in a kit. In some embodiments, kits may further include reagents and/or instructions for creating and/or synthesizing compounds and/or compositions of the present disclosure. In some embodiments, kits may also include one or more buffers. In some embodiments, kits may include components for making protein or nucleic acid arrays or libraries and thus, may include, for example, solid supports.

In some embodiments, kit components may be packaged either in aqueous media or in lyophilized form. The container means of the kits will generally include at least one vial, test tube, flask, bottle, syringe or other container means, into which a component may be placed, and preferably, suitably aliquoted. Where there is more than one kit component, (labeling reagent and label may be packaged together), kits may also generally contain second, third or other additional containers into which additional components may be separately placed. In some embodiments, kits may also comprise second container means for containing sterile, pharmaceutically acceptable buffers and/or other diluents. In some embodiments, various combinations of components may be comprised in one or more vial. Kits of the present disclosure may also typically include means for containing compounds and/or compositions of the present disclosure, e.g., proteins, nucleic acids, and any other reagent containers in close confinement for commercial sale. Such containers may include injection or blow-molded plastic containers into which desired vials are retained.

In some embodiments, kit components are provided in one and/or more liquid solutions. In some embodiments, liquid solutions are aqueous solutions, with sterile aqueous solutions being particularly preferred. In some embodiments, kit components may be provided as dried powder(s). When reagents and/or components are provided as dry powders, such powders may be reconstituted by the addition of suitable volumes of solvent. In some embodiments, it is envisioned that solvents may also be provided in another container means. In some embodiments, labeling dyes are provided as dried powders. In some embodiments, it is contemplated that 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 120, 130, 140, 150, 160, 170, 180, 190, 200, 300, 400, 500, 600, 700, 800, 900, 1000 micrograms or at least or at most those amounts of dried dye are provided in kits. In such embodiments, dye may then be resuspended in any suitable solvent, such as DMSO.

In some embodiments, kits may include instructions for employing kit components as well the use of any other reagent not included in the kit. Instructions may include variations that may be implemented.

Devices

In some embodiments, the AAV particles may delivered to a subject using a device to deliver the AAV particles and a head fixation assembly. The head fixation assembly may be, but is not limited to, any of the head fixation assemblies sold by MRI interventions. As a non-limiting example, the head fixation assembly may be any of the assemblies described in U.S. Pat. Nos. 8,099,150, 8,548,569, and 9,031,636 and International Patent Publication Nos. WO201108495 and WO2014014585, the contents of each of which are incorporated by reference in their entireties. A head fixation assembly may be used in combination with an MRI compatible drill such as, but not limited to, the MRI compatible drills described in International Patent Publication No. WO2013181008 and US Patent Publication No. US20130325012, the contents of which are herein incorporated by reference in its entirety.

In some embodiments, the AAV particles may be delivered using a method, system and/or computer program for positioning apparatus to a target point on a subject to deliver the AAV particles. As a non-limiting example, the method, system and/or computer program may be the methods, systems and/or computer programs described in U.S. Pat. No. 8,340,743, the contents of which are herein incorporated by reference in its entirety. The method may include: determining a target point in the body and a reference point, wherein the target point and the reference point define a planned trajectory line (PTL) extending through each; determining a visualization plane, wherein the PTL intersects the visualization plane at a sighting point: mounting the guide device relative to the body to move with respect to the PTL, wherein the guide device does not intersect the visualization plane: determining a point of intersection (GPP) between the guide axis and the visualization plane; and aligning the GPP with the sighting point in the visualization plane.

In some embodiments, the AAV particles may be delivered to a subject using a convention-enhanced delivery device. Non-limiting examples of targeted delivery of drugs using convection are described in US Patent Publication Nos. US20100217228, US20130035574, and US 20130035660 and International Patent Publication No. WO2013019830 and WO2008144585, the contents of each of which are herein incorporated by reference in their entireties.

In some embodiments, a subject may be imaged prior to, during and/or after delivery of the AAV particles. The imaging method may be a method known in the art and/or described herein, such as but not limited to, magnetic resonance imaging (MRI). As a non-limiting example, imaging may be used to assess therapeutic effect. As another non-limiting example, imaging may be used for assisted delivery of AAV particles.

In some embodiments, the AAV particles may be delivered using an MRI-guided device. Non-limiting examples of MRI-guided devices are described in U.S. Pat. Nos. 9,055,884, 9,042,958, 8,886,288, 8,768,433, 8,396,532, 8,369,930, 8,374,677, and 8,175,677 and US Patent Application No. US20140024927 the contents of each of which are herein incorporated by reference in their entireties. As a non-limiting example, the MRI-guided device may be able to provide data in real time such as those described in U.S. Pat. Nos. 8,886,288 and 8,768,433, the contents of each of which is herein incorporated by reference in its entirety. As another non-limiting example, the MRI-guided device or system may be used with a targeting cannula such as the systems described in U.S. Pat. Nos. 8,175,677 and 8,374,677, the contents of each of which are herein incorporated by reference in their entireties. As yet another non-limiting example, the MRI-guided device includes a trajectory guide frame for guiding an interventional device as described, for example, in U.S. Pat. No. 9,055,884 and US Patent Application No. US20140024927, the contents of each of which are herein incorporated by reference in their entireties.

In some embodiments, the AAV particles may be delivered using an MRI-compatible tip assembly. Non-limiting examples of MRI-compatible tip assemblies are described in US Patent Publication No. US20140275980, the contents of which is herein incorporated by reference in its entirety.

In some embodiments, the AAV particles may be delivered using a cannula which is MRI-compatible. Non-limiting examples of MRI-compatible cannulas include those taught in International Patent Publication No. WO2011130107, the contents of which are herein incorporated by reference in its entirety.

In some embodiments, the AAV particles may be delivered using a catheter which is MRI-compatible. Non-limiting examples of MRI-compatible catheters include those taught in International Patent Publication No. WO2012116265, U.S. Pat. No. 8,825,133 and US Patent Publication No. US20140024909, the contents of each of which are herein incorporated by reference in their entireties.

In some embodiments, the AAV particles may be delivered using a device with an elongated tubular body and a diaphragm as described in US Patent Publication Nos. US20140276582 and US20140276614, the contents of each of which are herein incorporated by reference in their entireties.

In some embodiments, the AAV particles may be delivered using an MRI compatible localization and/or guidance system such as, but not limited to, those described in US Patent Publication Nos. US20150223905 and US20150230871, the contents of each of which are herein incorporated by reference in their entireties. As a non-limiting example, the MRI compatible localization and/or guidance systems may comprise a mount adapted for fixation to a patient, a targeting cannula with a lumen configured to attach to the mount so as to be able to controllably translate in at least three dimensions, and an elongate probe configured to snugly advance via slide and retract in the targeting cannula lumen, the elongate probe comprising at least one of a stimulation or recording electrode.

In some embodiments, the AAV particles may be delivered to a subject using a trajectory frame as described in US Patent Publication Nos. US20150031982 and US20140066750 and International Patent Publication Nos. WO2015057807 and WO2014039481, the contents of each of which are herein incorporated by reference in their entireties.

In some embodiments, the AAV particles may be delivered to a subject using a gene gun.

VI. Definitions

At various places in the present specification, substituents of compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every individual sub combination of the members of such groups and ranges.

About: As used herein, the term “about” means +/−10% of the recited value.

Adeno-associated virus: The term “adeno-associated virus” or “AAV” as used herein refers to members of the dependovirus genus comprising any particle, sequence, gene, protein, or component derived therefrom.

AA6V Particle: As used herein, an “AAV particle” is a virus which comprises a viral genome with at least one payload region and at least one ITR region. AAV vectors of the present disclosure may be produced recombinantly and may be based on adeno-associated virus (AAV) parent or reference sequences. AAV particle may be derived from any serotype, described herein or known in the art, including combinations of serotypes (i.e., “pseudotyped” AAV) or from various genomes (e.g., single stranded or self-complementary). In addition, the AAV particle may be replication defective and/or targeted.

Activity: As used herein, the term “activity” refers to the condition in which things are happening or being done. Compositions may have activity and this activity may involve one or more biological events.

Administered in combination: As used herein, the term “administered in combination” or “combined administration” means that two or more agents are administered to a subject at the same time or within an interval such that there may be an overlap of an effect of each agent on the patient. In some embodiments, they are administered within about 60, 30, 15, 10, 5, or 1 minute of one another. In some embodiments, the administrations of the agents are spaced sufficiently closely together such that a combinatorial (e.g., a synergistic) effect is achieved.

Amelioration: As used herein, the term “amelioration” or “ameliorating” refers to a lessening of severity of at least one indicator of a condition or disease. For example, in the context of neurodegeneration disorder, amelioration includes the reduction of neuron loss.

Animal: As used herein, the term “animal” refers to any member of the animal kingdom. In some embodiments, “animal” refers to humans at any stage of development. In some embodiments, “animal” refers to non-human animals at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, and worms. In some embodiments, the animal is a transgenic animal, genetically-engineered animal, or a clone.

Antibody: As used herein, the term “antibody” is referred to in the broadest sense and specifically covers various embodiments including, but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g. bispecific antibodies formed from at least two intact antibodies), and antibody fragments (e.g., diabodies) so long as they exhibit a desired biological activity (e.g., “functional”). Antibodies are primarily amino-acid based molecules but may also comprise one or more modifications (including, but not limited to the addition of sugar moieties, fluorescent moieties, chemical tags, etc.). Non-limiting examples of antibodies or fragments thereof include V_(H) and VL domains, scFvs, Fab, Fab′, F(ab′)₂, Fv fragment, diabodies, linear antibodies, single chain antibody molecules, multispecific antibodies, bispecific antibodies, intrabodies, monoclonal antibodies, polyclonal antibodies, humanized antibodies, codon-optimized antibodies, tandem scFv antibodies, bispecific T-cell engagers, mAb2 antibodies, chimeric antigen receptors (CAR), tetravalent bispecific antibodies, biosynthetic antibodies, native antibodies, miniaturized antibodies, unibodies, maxibodies, antibodies to senescent cells, antibodies to conformers, antibodies to disease specific epitopes, or antibodies to innate defense molecules.

Antibody-based composition: As used herein, “antibody-based” or “antibody-derived” compositions are monomeric or multi-meric polypeptides which comprise at least one amino-acid region derived from a known or parental antibody sequence and at least one amino acid region derived from a non-antibody sequence, e.g., mammalian protein.

Approximately: As used herein, the term “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

Associated with: As used herein, the terms “associated with,” “conjugated,” “linked,” “attached,” and “tethered,” when used with respect to two or more moieties, means that the moieties are physically associated or connected with one another, either directly or via one or more additional moieties that serves as a linking agent, to form a structure that is sufficiently stable so that the moieties remain physically associated under the conditions in which the structure is used, e.g., physiological conditions. An “association” need not be strictly through direct covalent chemical bonding. It may also suggest ionic or hydrogen bonding or a hybridization based connectivity sufficiently stable such that the “associated” entities remain physically associated.

Bifunctional: As used herein, the term “bifunctional” refers to any substance, molecule or moiety which is capable of or maintains at least two functions. The functions may affect the same outcome or a different outcome. The structure that produces the function may be the same or different.

Biocompatible: As used herein, the term “biocompatible” means compatible with living cells, tissues, organs or systems posing little to no risk of injury, toxicity or rejection by the immune system.

Biodegradable: As used herein, the term “biodegradable” means capable of being broken down into innocuous products by the action of living things.

Biologically active: As used herein, the phrase “biologically active” refers to a characteristic of any substance that has activity in a biological system and/or organism. For instance, a substance that, when administered to an organism, has a biological effect on that organism, is considered to be biologically active. In particular embodiments, an AAV particle of the present disclosure may be considered biologically active if even a portion of the encoded payload is biologically active or mimics an activity considered biologically relevant.

Capsid: As used herein, the term “capsid” refers to the protein shell of a virus particle. In some embodiments, the term capsid may refer to the nucleic acid encoding the protein shell of the virus particle.

Chimeric antigen receptor (CAR): As used herein, the term “chimeric antigen receptor” or “CAR” refers to an artificial chimeric protein comprising at least one antigen specific targeting region (ASTR), a transmembrane domain and an intracellular signaling domain, wherein the antigen specific targeting region comprises a full-length antibody or a fragment thereof. As a non-limiting example, the ASTR of a CAR may be any of the antibodies listed in Table 3, antibody-based compositions or fragments thereof. Any molecule that is capable of binding a target antigen with high affinity can be used in the ASTR of a CAR. The CAR may optionally have an extracellular spacer domain and/or a co-stimulatory domain. A CAR may also be used to generate a cytotoxic cell carrying the CAR.

Complementary and substantially complementary: As used herein, the term “complementary” refers to the ability of polynucleotides to form base pairs with one another. Base pairs are typically formed by hydrogen bonds between nucleotide units in antiparallel polynucleotide strands. Complementary polynucleotide strands can form base pair in the Watson-Crick manner (e.g., A to T. A to U, C to G), or in any other manner that allows for the formation of duplexes. As persons skilled in the art are aware, when using RNA as opposed to DNA, uracil rather than thymine is the base that is considered to be complementary to adenosine. However, when a U is denoted in the context of the present disclosure, the ability to substitute a T is implied, unless otherwise stated. Perfect complementarity or 100% complementarity refers to the situation in which each nucleotide unit of one polynucleotide strand can form hydrogen bond with a nucleotide unit of a second polynucleotide strand. Less than perfect complementarity refers to the situation in which some, but not all, nucleotide units of two strands can form hydrogen bond with each other. For example, for two 20-mers, if only two base pairs on each strand can form hydrogen bond with each other, the polynucleotide strands exhibit 10% complementarity. In the same example, if 18 base pairs on each strand can form hydrogen bonds with each other, the polynucleotide strands exhibit 90% complementarity. As used herein, the term “substantially complementary” means that the siRNA has a sequence (e.g., in the antisense strand) which is sufficient to bind the desired target mRNA, and to trigger the RNA silencing of the target mRNA.

Compound: Compounds of the present disclosure include all of the isotopes of the atoms occurring in the intermediate or final compounds. “Isotopes” refers to atoms having the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei. For example, isotopes of hydrogen include tritium and deuterium.

The compounds and salts of the present disclosure can be prepared in combination with solvent or water molecules to form solvates and hydrates by routine methods.

Comprehensive Positional Evolution (CPE™): As used herein, the term “comprehensive positional evolution” refers to an antibody evolution technology that allows for mapping of the effects of amino acid changes at every position along an antibody variable domain's sequence. This comprehensive mutagenesis technology can be used to enhance one or more antibody properties or characteristics.

Comprehensive Protein Synthesis (CPS™): As used herein, the term “comprehensive protein synthesis” refers to a combinatorial protein synthesis technology that can be used to optimize antibody properties or characteristics by combining the best properties into a new, high-performance antibody.

Conditionally active: As used herein, the term “conditionally active” refers to a mutant or variant of a wild-type polypeptide, wherein the mutant or variant is more or less active at physiological conditions than the parent polypeptide. Further, the conditionally active polypeptide may have increased or decreased activity at aberrant conditions as compared to the parent polypeptide. A conditionally active polypeptide may be reversibly or irreversibly inactivated at normal physiological conditions or aberrant conditions.

Conserved: As used herein, the term “conserved” refers to nucleotides or amino acid residues of a polynucleotide sequence or polypeptide sequence, respectively, that are those that occur unaltered in the same position of two or more sequences being compared. Nucleotides or amino acids that are relatively conserved are those that are conserved amongst more related sequences than nucleotides or amino acids appearing elsewhere in the sequences.

In some embodiments, two or more sequences are said to be “completely conserved” if they are 100% identical to one another. In some embodiments, two or more sequences are said to be “highly conserved” if they are at least 70% identical, at least 80% identical, at least 90% identical, or at least 95% identical to one another. In some embodiments, two or more sequences are said to be “highly conserved” if they are about 70% identical, about 80% identical, about 90% identical, about 95%, about 98%, or about 99% identical to one another. In some embodiments, two or more sequences are said to be “conserved” if they are at least 30% identical, at least 40% identical, at least 50% identical, at least 60% identical, at least 70% identical, at least 80% identical, at least 90% identical, or at least 95% identical to one another. In some embodiments, two or more sequences are said to be “conserved” if they are about 30% identical, about 40% identical, about 50% identical, about 60% identical, about 70% identical, about 80% identical, about 90% identical, about 95% identical, about 98% identical, or about 99% identical to one another. Conservation of sequence may apply to the entire length of a polynucleotide or polypeptide or may apply to a portion, region or feature thereof.

Control Elements: As used herein, “control elements”, “regulatory control elements”, or “regulatory sequences” refers to promoter regions, polyadenylation signals, transcription termination sequences, upstream regulatory domains, origins of replication, internal ribosome entry sites (“IRES”), enhancers, and the like, which provide for the replication, transcription and translation of a coding sequence in a recipient cell. Not all of these control elements need always be present as long as the selected coding sequence is capable of being replicated, transcribed and/or translated in an appropriate host cell.

Controlled Release: As used herein, the term “controlled release” refers to a pharmaceutical composition or compound release profile that conforms to a particular pattern of release to affect a therapeutic outcome.

Cytostatic: As used herein, “cytostatic” refers to inhibiting, reducing, suppressing the growth, division, or multiplication of a cell (e.g., a mammalian cell (e.g., a human cell)), bacterium, virus, fungus, protozoan, parasite, prion, or a combination thereof.

Cytotoxic: As used herein, “cytotoxic” refers to killing or causing injurious, toxic, or deadly effect on a cell (e.g., a mammalian cell (e.g., a human cell)), bacterium, virus, fungus, protozoan, parasite, prion, or a combination thereof.

Delivery: As used herein, “delivery” refers to the act or manner of delivering an AAV particle, a compound, substance, entity, moiety, cargo or payload.

Delivery Agent: As used herein, “delivery agent” refers to any substance which facilitates, at least in part, the in vivo delivery of an AAV particle to targeted cells.

Destabilized: As used herein, the term “destable”, “destabilize”, or “destabilizing region” means a region or molecule that is less stable than a starting, wild-type or native form of the same region or molecule.

Detectable label: As used herein, “detectable label” refers to one or more markers, signals, or moieties which are attached, incorporated or associated with another entity that is readily detected by methods known in the art including radiography, fluorescence, chemiluminescence, enzymatic activity, absorbance and the like. Detectable labels include radioisotopes, fluorophores, chromophores, enzymes, dyes, metal ions, ligands such as biotin, avidin, streptavidin and haptens, quantum dots, and the like. Detectable labels may be located at any position in the peptides or proteins disclosed herein. They may be within the amino acids, the peptides, or proteins, or located at the N- or C-termini.

Digest: As used herein, the term “digest” means to break apart into smaller pieces or components. When referring to polypeptides or proteins, digestion results in the production of peptides.

Distal: As used herein, the term “distal” means situated away from the center or away from a point or region of interest.

Dosing regimen: As used herein, a “dosing regimen” is a schedule of administration or physician determined regimen of treatment, prophylaxis, or palliative care.

Encapsulate: As used herein, the term “encapsulate” means to enclose, surround or encase.

Engineered: As used herein, embodiments are “engineered” when they are designed to have a feature or property, whether structural or chemical, that varies from a starting point, wild type or native molecule.

Effective Amount: As used herein, the term “effective amount” of an agent is that amount sufficient to effect beneficial or desired results, for example, clinical results, and, as such, an “effective amount” depends upon the context in which it is being applied. For example, in the context of administering an agent that treats cancer, an effective amount of an agent is, for example, an amount sufficient to achieve treatment, as defined herein, of cancer, as compared to the response obtained without administration of the agent.

Epitope: As used herein, an “epitope” refers to a surface or region on a molecule that is capable of interacting with a biomolecule. For example, a protein may contain one or more amino acids, e.g., an epitope, which interacts with an antibody. e.g., a biomolecule. In some embodiments, when referring to a protein or protein module, an epitope may comprise a linear stretch of amino acids or a three-dimensional structure formed by folded amino acid chains.

EvoMap™: As used herein, an EvoMap™ refers to a map of a polypeptide, wherein detailed informatics are presented about the effects of single amino acid mutations within the length of the polypeptide and their influence on the properties and characteristics of that polypeptide.

Expression: As used herein, “expression” of a nucleic acid sequence refers to one or more of the following events: (1) production of an RNA template from a DNA sequence (e.g., by transcription); (2) processing of an RNA transcript (e.g., by splicing, editing, 5′ cap formation, and/or 3′ end processing): (3) translation of an RNA into a polypeptide or protein; and (4) post-translational modification of a polypeptide or protein.

Feature: As used herein, a “feature” refers to a characteristic, a property, or a distinctive element.

Formulation: As used herein, a “formulation” includes at least one AAV particle and a delivery agent.

Fragment: A “fragment.” as used herein, refers to a portion. For example, fragments of proteins may comprise polypeptides obtained by digesting full-length protein isolated from cultured cells.

Functional: As used herein, a “functional” biological molecule is a biological molecule in a form in which it exhibits a property and/or activity by which it is characterized.

Gene expression: The term “gene expression” refers to the process by which a nucleic acid sequence undergoes successful transcription and in most instances translation to produce a protein or peptide. For clarity, when reference is made to measurement of “gene expression”, this should be understood to mean that measurements may be of the nucleic acid product of transcription, e.g., RNA or mRNA or of the amino acid product of translation, e.g., polypeptides or peptides. Methods of measuring the amount or levels of RNA, mRNA, polypeptides and peptides are well known in the art.

Homology: As used herein, the term “homology” refers to the overall relatedness between polymeric molecules, e.g. between polynucleotide molecules (e.g. DNA molecules and/or RNA molecules) and/or between polypeptide molecules. In some embodiments, polymeric molecules are considered to be “homologous” to one another if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical or similar. The term “homologous” necessarily refers to a comparison between at least two sequences (polynucleotide or polypeptide sequences). In accordance with the disclosure, two polynucleotide sequences are considered to be homologous if the polypeptides they encode are at least about 50%, 60%, 70%, 80%, 90%, 95%, or even 99% for at least one stretch of at least about 20 amino acids. In some embodiments, homologous polynucleotide sequences are characterized by the ability to encode a stretch of at least 4-5 uniquely specified amino acids. For polynucleotide sequences less than 60 nucleotides in length, homology is determined by the ability to encode a stretch of at least 4-5 uniquely specified amino acids. In accordance with the disclosure, two protein sequences are considered to be homologous if the proteins are at least about 50%, 60%, 70%, 80%, or 90% identical for at least one stretch of at least about 20 amino acids.

Heterologous Region: As used herein the term “heterologous region” refers to a region which would not be considered a homologous region.

Homologous Region: As used herein the term “homologous region” refers to a region which is similar in position, structure, evolution origin, character, form or function.

Identity: As used herein, the term “identity” refers to the overall relatedness between polymeric molecules, e.g., between polynucleotide molecules (e.g. DNA molecules and/or RNA molecules) and/or between polypeptide molecules. Calculation of the percent identity of two polynucleotide sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second nucleic acid sequences for optimal alignment and non-identical sequences can be disregarded for comparison purposes). In certain embodiments, the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100/0 of the length of the reference sequence. The nucleotides at corresponding nucleotide positions are then compared. When a position in the first sequence is occupied by the same nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which needs to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. For example, the percent identity between two nucleotide sequences can be determined using methods such as those described in Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith. D. W., ed., Academic Press, New York, 1993; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; Computer Analysis of Sequence Data, Part I, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; and Sequence Analysis Primer, Gribskov. M. and Devereux. J., eds., M Stockton Press, New York, 1991; each of which is incorporated herein by reference. For example, the percent identity between two nucleotide sequences can be determined using the algorithm of Meyers and Miller (CABIOS, 1989, 4:11-17), which has been incorporated into the ALIGN program (version 2.0) using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. The percent identity between two nucleotide sequences can, alternatively, be determined using the GAP program in the GCG software package using an NWSgapdna.CMP matrix. Methods commonly employed to determine percent identity between sequences include, but are not limited to those disclosed in Carillo, H. and Lipman, D., SIAM J Applied Math., 48:1073 (1988); incorporated herein by reference. Techniques for determining identity are codified in publicly available computer programs. Exemplary computer software to determine homology between two sequences include, but are not limited to, GCG program package, Devereux, J., el al., Nucleic Acids Research, 12(1), 387 (1984)), BLASTP, BLASTN, and FASTA Altschul, S. F. et al., J. Molec. Biol., 215, 403 (1990)).

Inhibit expression of a gene: As used herein, the phrase “inhibit expression of a gene” means to cause a reduction in the amount of an expression product of the gene. The expression product can be an RNA transcribed from the gene (e.g., an mRNA) or a polypeptide translated from an mRNA transcribed from the gene. Typically, a reduction in the level of an mRNA results in a reduction in the level of a polypeptide translated therefrom. The level of expression may be determined using standard techniques for measuring mRNA or protein.

In vitro: As used herein, the term “in vitro” refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, in a Petri dish, etc., rather than within an organism (e.g., animal, plant, or microbe).

In vivo: As used herein, the term “in vivo” refers to events that occur within an organism (e.g., animal, plant, or microbe or cell or tissue thereof).

Isolated: As used herein, the term “isolated” refers to a substance or entity that has been separated from at least some of the components with which it was associated (whether in nature or in an experimental setting). Isolated substances may have varying levels of purity in reference to the substances from which they have been associated. Isolated substances and/or entities may be separated from at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more of the other components with which they were initially associated. In some embodiments, isolated agents are more than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% pure. As used herein, a substance is “pure” if it is substantially free of other components.

Substantially isolated: By “substantially isolated” is meant that a substance is substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the substance or AAV particles of the present disclosure. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the present disclosure, or salt thereof. Methods for isolating compounds and their salts are routine in the art.

Linker: As used herein “linker” refers to a molecule or group of molecules which connects two molecules, such as a V_(H) chain and V_(L) chain or an antibody. A linker may be a nucleic acid sequence connecting two nucleic acid sequences encoding two different polypeptides. The linker may or may not be translated. The linker may be a cleavable linker.

MicroRNA (miRNA) binding site: As used herein, a microRNA (miRNA) binding site represents a nucleotide location or region of a nucleic acid transcript to which at least the “seed” region of a miRNA binds.

Modified: As used herein “modified” refers to a changed state or structure of a molecule. Molecules may be modified in many ways including chemically, structurally, and functionally.

Naturally Occurring: As used herein, “naturally occurring” or “wild-type” means existing in nature without artificial aid, or involvement of the hand of man.

Non-human vertebrate: As used herein, a “non-human vertebrate” includes all vertebrates except Homo sapiens, including wild and domesticated species. Examples of non-human vertebrates include, but are not limited to, mammals, such as alpaca, banteng, bison, camel, cat, cattle, deer, dog, donkey, gayal, goat, guinea pig, horse, llama, mule, pig, rabbit, reindeer, sheep water buffalo, and yak.

Off-target: As used herein, “off target” refers to any unintended effect on any one or more target, gene, or cellular transcript.

Open reading frame: As used herein, “open reading frame” or “ORF” refers to a sequence which does not contain a stop codon in a given reading frame.

Operably linked: As used herein, the phrase “operably linked” refers to a functional connection between two or more molecules, constructs, transcripts, entities, moieties or the like.

Particle: As used herein, a “particle” is a virus comprised of at least two components, a protein capsid and a polynucleotide sequence enclosed within the capsid (e.g., viral genome).

Patient: As used herein, “patient” refers to a subject who may seek or be in need of treatment, requires treatment, is receiving treatment, will receive treatment, or a subject who is under care by a trained professional for a particular disease or condition.

Payload: As used herein, “payload” or “payload region” refers to one or more polynucleotides or polynucleotide regions encoded by or within a viral genome or an expression product of such polynucleotide or polynucleotide region, e.g., a transgene, a polynucleotide encoding a polypeptide or multi-polypeptide or a modulatory nucleic acid or regulatory nucleic acid.

Payload construct: As used herein, “payload construct” or “construct” is one or more polynucleotide regions encoding or comprising a payload that is flanked on one or both sides by an inverted terminal repeat (ITR) sequence. The payload construct is a template that is replicated in a viral production cell to produce a viral genome.

Payload construct vector: As used herein, “payload construct vector” is a vector encoding or comprising a payload construct, and regulatory regions for replication and expression in bacterial cells.

Payload construct expression vector: As used herein, a “payload construct expression vector” is a vector encoding or comprising a payload construct and which further comprises one or more polynucleotide regions encoding or comprising components for viral expression in a viral replication cell.

Peptide: As used herein, “peptide” is less than or equal to 50 amino acids long, e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 amino acids long.

Pharmaceutically acceptable: The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable excipients: The phrase “pharmaceutically acceptable excipient.” as used herein, refers any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

Pharmaceutically acceptable salts: The present disclosure also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form (e.g., by reacting the free base group with a suitable organic acid). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Representative acid addition salts include acetate, acetic acid, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzene sulfonic acid, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17^(th) ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, Pharmaceutical Salts: Properties, Selection, and Use, P. H. Stahl and C. G. Wermuth (eds.), Wiley-VCH, 2008, and Berge et al., Journal of Pharmaceutical Science, 66, 1-19 (1977), each of which is incorporated herein by reference in its entirety.

Pharmaceutically acceptable solvate: The term “pharmaceutically acceptable solvate,” as used herein, means a compound wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered. For example, solvates may be prepared by crystallization, recrystallization, or precipitation from a solution that includes organic solvents, water, or a mixture thereof. Examples of suitable solvents are ethanol, water (for example, mono-, di-, and tri-hydrates), N-methylpyrrolidinone (NMP), dimethyl sulfoxide (DMSO), N,N′-dimethylformamide (DMF), N,N′-dimethylacetamide (DMAC), 1,3-dimethyl-2-imidazolidinone (DMEU), 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone (DMPU), acetonitrile (ACN), propylene glycol, ethyl acetate, benzyl alcohol, 2-pyrrolidone, benzyl benzoate, and the like. When water is the solvent, the solvate is referred to as a “hydrate.”

Pharmacokinetic: As used herein, “pharmacokinetic” refers to any one or more properties of a molecule or compound as it relates to the determination of the fate of substances administered to a living organism. Pharmacokinetics is divided into several areas including the extent and rate of absorption, distribution, metabolism and excretion. This is commonly referred to as ADME where: (A) Absorption is the process of a substance entering the blood circulation; (D) Distribution is the dispersion or dissemination of substances throughout the fluids and tissues of the body; (M) Metabolism (or Biotransformation) is the irreversible transformation of parent compounds into daughter metabolites; and (E) Excretion (or Elimination) refers to the elimination of the substances from the body. In rare cases, some drugs irreversibly accumulate in body tissue.

Physicochemical: As used herein, “physicochemical” means of or relating to a physical and/or chemical property.

Preventing: As used herein, the term “preventing” refers to partially or completely delaying onset of an infection, disease, disorder and/or condition: partially or completely delaying onset of one or more symptoms, features, or clinical manifestations of a particular infection, disease, disorder, and/or condition: partially or completely delaying onset of one or more symptoms, features, or manifestations of a particular infection, disease, disorder, and/or condition; partially or completely delaying progression from an infection, a particular disease, disorder and/or condition; and/or decreasing the risk of developing pathology associated with the infection, the disease, disorder, and/or condition.

Proliferate: As used herein, the term “proliferate” means to grow, expand or increase or cause to grow, expand or increase rapidly. “Proliferative” means having the ability to proliferate. “Anti-proliferative” means having properties counter to or inapposite to proliferative properties.

Prophylactic: As used herein, “prophylactic” refers to a therapeutic or course of action used to prevent the spread of disease.

Prophylaxis: As used herein, a “prophylaxis” refers to a measure taken to maintain health and prevent the spread of disease.

Protein of interest: As used herein, the terms “proteins of interest” or “desired proteins” include those provided herein and fragments, mutants, variants, and alterations thereof.

Proximal: As used herein, the term “proximal” means situated nearer to the center or to a point or region of interest.

Purified: As used herein, “purify,” “purified,” “purification” means to make substantially pure or clear from unwanted components, material defilement, admixture or imperfection. “Purified” refers to the state of being pure. “Purification” refers to the process of making pure.

Region: As used herein, the term “region” refers to a zone or general area. In some embodiments, when referring to a protein or protein module, a region may comprise a linear sequence of amino acids along the protein or protein module or may comprise a three-dimensional area, an epitope and/or a cluster of epitopes. In some embodiments, regions comprise terminal regions. As used herein, the term “terminal region” refers to regions located at the ends or termini of a given agent. When referring to proteins, terminal regions may comprise N- and/or C-termini. N-termini refer to the end of a protein comprising an amino acid with a free amino group. C-termini refer to the end of a protein comprising an amino acid with a free carboxyl group. N- and/or C-terminal regions may there for comprise the N- and/or C-termini as well as surrounding amino acids. In some embodiments, N- and/or C-terminal regions comprise from about 3 amino acid to about 30 amino acids, from about 5 amino acids to about 40 amino acids, from about 10 amino acids to about 50 amino acids, from about 20 amino acids to about 100 amino acids and/or at least 100 amino acids. In some embodiments, N-terminal regions may comprise any length of amino acids that includes the N-terminus, but does not include the C-terminus. In some embodiments, C-terminal regions may comprise any length of amino acids, which include the C-terminus, but do not comprise the N-terminus.

In some embodiments, when referring to a polynucleotide, a region may comprise a linear sequence of nucleic acids along the polynucleotide or may comprise a three-dimensional area, secondary structure, or tertiary structure. In some embodiments, regions comprise terminal regions. As used herein, the term “terminal region” refers to regions located at the ends or termini of a given agent. When referring to polynucleotides, terminal regions may comprise 5′ and 3′ termini, 5′ termini refer to the end of a polynucleotide comprising a nucleic acid with a free phosphate group. 3′ termini refer to the end of a polynucleotide comprising a nucleic acid with a free hydroxyl group. 5′ and 3′ regions may there for comprise the 5′ and 3′ termini as well as surrounding nucleic acids. In some embodiments, 5′ and 3′ terminal regions comprise from about 9 nucleic acids to about 90 nucleic acids, from about 15 nucleic acids to about 120 nucleic acids, from about 30 nucleic acids to about 150 nucleic acids, from about 60 nucleic acids to about 300 nucleic acids and/or at least 300 nucleic acids. In some embodiments, 5′ regions may comprise any length of nucleic acids that includes the 5′ terminus, but does not include the 3′ terminus. In some embodiments, 3′ regions may comprise any length of nucleic acids, which include the 3′ terminus, but does not comprise the 5′ terminus.

RNA or RNA molecule: As used herein, the term “RNA” or “RNA molecule” or “ribonucleic acid molecule” refers to a polymer of ribonucleotides; the term “DNA” or “DNA molecule” or “deoxyribonucleic acid molecule” refers to a polymer of deoxyribonucleotides. DNA and RNA can be synthesized naturally, e.g., by DNA replication and transcription of DNA, respectively; or be chemically synthesized. DNA and RNA can be single-stranded (i.e., ssRNA or ssDNA, respectively) or multi-stranded (e.g., double stranded, i.e., dsRNA and dsDNA, respectively). The term “mRNA” or “messenger RNA”, as used herein, refers to a single stranded RNA that encodes the amino acid sequence of one or more polypeptide chains.

Sample: As used herein, the term “sample” or “biological sample” refers to a subset of its tissues, cells or component parts (e.g. body fluids, including but not limited to blood, mucus, lymphatic fluid, synovial fluid, cerebrospinal fluid, saliva, amniotic fluid, amniotic cord blood, urine, vaginal fluid and semen). A sample further may include a homogenate, lysate or extract prepared from a whole organism or a subset of its tissues, cells or component parts, or a fraction or portion thereof, including but not limited to, for example, plasma, serum, spinal fluid, lymph fluid, the external sections of the skin, respiratory, intestinal, and genitourinary tracts, tears, saliva, milk, blood cells, tumors, organs. A sample further refers to a medium, such as a nutrient broth or gel, which may contain cellular components, such as proteins or nucleic acid molecule.

Self-complementary viral particle: As used herein, a “self-complementary viral particle” is a particle comprised of at least two components, a protein capsid and a polynucleotide sequence encoding a self-complementary genome enclosed within the capsid.

Signal Sequences: As used herein, the phrase “signal sequences” refers to a sequence which can direct the transport or localization of a protein.

Single unit dose: As used herein, a “single unit dose” is a dose of any therapeutic administered in one dose/at one time/single route/single point of contact, i.e., single administration event. In some embodiments, a single unit dose is provided as a discrete dosage form (e.g., a tablet, capsule, patch, loaded syringe, vial, etc.).

Similarity: As used herein, the term “similarity” refers to the overall relatedness between polymeric molecules, e.g. between polynucleotide molecules (e.g. DNA molecules and/or RNA molecules) and/or between polypeptide molecules. Calculation of percent similarity of polymeric molecules to one another can be performed in the same manner as a calculation of percent identity, except that calculation of percent similarity takes into account conservative substitutions as is understood in the art.

Split dose: As used herein, a “split dose” is the division of single unit dose or total daily dose into two or more doses.

Stable: As used herein “stable” refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent.

Stabilized: As used herein, the term “stabilize”, “stabilized.” “stabilized region” means to make or become stable.

Subject: As used herein, the term “subject” or “patient” refers to any organism to which a composition in accordance with the disclosure may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans) and/or plants.

Substantially: As used herein, the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result. The term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

Substantially equal: As used herein as it relates to time differences between doses, the term means plus/minus 2%.

Substantially simultaneously: As used herein and as it relates to plurality of doses, the term means within 2 seconds.

Suffering from: An individual who is “suffering from” a disease, disorder, and/or condition has been diagnosed with or displays one or more symptoms of a disease, disorder, and/or condition.

Susceptible to: An individual who is “susceptible to” a disease, disorder, and/or condition has not been diagnosed with and/or may not exhibit symptoms of the disease, disorder, and/or condition but harbors a propensity to develop a disease or its symptoms. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition (for example, cancer) may be characterized by one or more of the following: (1) a genetic mutation associated with development of the disease, disorder, and/or condition; (2) a genetic polymorphism associated with development of the disease, disorder, and/or condition; (3) increased and/or decreased expression and/or activity of a protein and/or nucleic acid associated with the disease, disorder, and/or condition; (4) habits and/or lifestyles associated with development of the disease, disorder, and/or condition; (5) a family history of the disease, disorder, and/or condition; and (6) exposure to and/or infection with a microbe associated with development of the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition will develop the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition will not develop the disease, disorder, and/or condition.

Sustained release: As used herein, the term “sustained release” refers to a pharmaceutical composition or compound release profile that conforms to a release rate over a specific period of time.

Synthetic: The term “synthetic” means produced, prepared, and/or manufactured by the hand of man. Synthesis of polynucleotides or polypeptides or other molecules of the present disclosure may be chemical or enzymatic.

Targeting: As used herein, “targeting” means the process of design and selection of nucleic acid sequence that will hybridize to a target nucleic acid and induce a desired effect.

Targeted Cells: As used herein, “targeted cells” refers to any one or more cells of interest. The cells may be found in vitro, in vivo, in situ or in the tissue or organ of an organism. The organism may be an animal, preferably a mammal, more preferably a human and most preferably a patient.

Therapeutic Agent: The term “therapeutic agent” refers to any agent that, when administered to a subject, has a therapeutic, diagnostic, and/or prophylactic effect and/or elicits a desired biological and/or pharmacological effect.

Therapeutically effective amount: As used herein, the term “therapeutically effective amount” means an amount of an agent to be delivered (e.g., nucleic acid, drug, therapeutic agent, diagnostic agent, prophylactic agent, etc.) that is sufficient, when administered to a subject suffering from or susceptible to an infection, disease, disorder, and/or condition, to treat, improve symptoms of, diagnose, prevent, and/or delay the onset of the infection, disease, disorder, and/or condition. In some embodiments, a therapeutically effective amount is provided in a single dose. In some embodiments, a therapeutically effective amount is administered in a dosage regimen comprising a plurality of doses. Those skilled in the art will appreciate that in some embodiments, a unit dosage form may be considered to comprise a therapeutically effective amount of a particular agent or entity if it comprises an amount that is effective when administered as part of such a dosage regimen.

Therapeutically effective outcome: As used herein, the term “therapeutically effective outcome” means an outcome that is sufficient in a subject suffering from or susceptible to an infection, disease, disorder, and/or condition, to treat, improve symptoms of, diagnose, prevent, and/or delay the onset of the infection, disease, disorder, and/or condition.

Total daily dose: As used herein, a “total daily dose” is an amount given or prescribed in 24 hr period. It may be administered as a single unit dose.

Transfection: As used herein, the term “transfection” refers to methods to introduce exogenous nucleic acids into a cell. Methods of transfection include, but are not limited to, chemical methods, physical treatments and cationic lipids or mixtures.

Treating: As used herein, the term “treating” refers to partially or completely alleviating, ameliorating, improving, relieving, delaying onset of, inhibiting progression of, reducing severity of, and/or reducing incidence of one or more symptoms or features of a particular infection, disease, disorder, and/or condition. For example, “treating” cancer may refer to inhibiting survival, growth, and/or spread of a tumor. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition and/or to a subject who exhibits only early signs of a disease, disorder, and/or condition for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition.

Unmodified: As used herein, “unmodified” refers to any substance, compound or molecule prior to being changed in any way. Unmodified may, but does not always, refer to the wild type or native form of a biomolecule. Molecules may undergo a series of modifications whereby each modified molecule may serve as the “unmodified” starting molecule for a subsequent modification.

Vector: As used herein, a “vector” is any molecule or moiety which transports, transduces or otherwise acts as a carrier of a heterologous molecule. Vectors of the present disclosure may be produced recombinantly and may be based on and/or may comprise adeno-associated virus (AAV) parent or reference sequence. Such parent or reference AAV sequences may serve as an original, second, third or subsequent sequence for engineering vectors. In non-limiting examples, such parent or reference AAV sequences may comprise any one or more of the following sequences: a polynucleotide sequence encoding a polypeptide or multi-polypeptide, which sequence may be wild-type or modified from wild-type and which sequence may encode full-length or partial sequence of a protein, protein domain, or one or more subunits of a protein; a polynucleotide comprising a modulatory or regulatory nucleic acid which sequence may be wild-type or modified from wild-type; and a transgene that may or may not be modified from wild-type sequence. These AAV sequences may serve as either the “donor” sequence of one or more codons (at the nucleic acid level) or amino acids (at the polypeptide level) or “acceptor” sequences of one or more codons (at the nucleic acid level) or amino acids (at the polypeptide level).

Viral genome: As used herein, a “viral genome” or “vector genome” is a polynucleotide comprising at least one inverted terminal repeat (ITR) and at least one encoded payload. A viral genome encodes at least one copy of the payload.

Described herein are compositions, methods, processes, kits and devices for the design, preparation, manufacture and/or formulation of AAV particles. In some embodiments, payloads, such as but not limited to AAV polynucleotides, may be encoded by payload constructs or contained within plasmids or vectors or recombinant adeno-associated viruses (AAVs).

The details of one or more embodiments are set forth in the accompanying description below. Although any materials and methods similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred materials and methods are now described. Other features, objects and advantages will be apparent from the description. In the description, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the case of conflict, the present description will control.

The present disclosure is further illustrated by the following non-limiting examples.

VII. Examples Example 1. Generation of Antibodies Antibody Production by Hybridoma Technology

Host animals (e.g. mice, rabbits, goats, and llamas) are immunized by an injection with an antigenic protein (e.g., tau) to elicit lymphocytes that specifically bind to the antigen (e.g., tau). Lymphocytes are collected and fused with immortalized cell lines to generate hybridomas. Hybridomas are cultured in a suitable culture medium that is enriched with appropriate selection agents to promote growth.

Antibodies produced by the cultured hybridomas are subjected to analysis to determine binding specificity of the antibodies for the target antigen. Once antibodies with desirable characteristics are identified, corresponding hybridomas are subcloned through limiting dilution procedures and grown by standard methods. Antibodies produced by these cells are isolated and purified using standard immunoglobulin purification procedures.

Tau knock-out mice and/or wild-type mice (CD1 or B6/129) are immunized with a tau antigen using the HT-Hock immunization method. The tau antigens are selected from, (1) ePHF, (2) a mid-domain tau peptide for targeting pathological forms of tau around T181-T217 of human 441 tau, (3) a C-terminal tau peptide for targeting pathological forms of tau around S396-S422, and (4) an AT100 immunopurified tau from human AD brain.

Recombinant Antibody Production

Recombinant antibodies are produced using heavy and light chain variable region cDNA sequences selected from hybridomas or from other sources. Sequences encoding antibody variable domains expressed by hybridomas are determined by extracting RNA molecules from antibody-producing hybridoma cells and producing cDNA by reverse transcriptase polymerase chain reaction (PCR). PCR is used to amplify cDNA using primers specific for heavy and light chain sequences. PCR products are then subcloned into plasmids for sequence analysis. Antibodies are produced by insertion of resulting variable domain sequences into expression vectors.

Recombinant antibodies are also produced using phage display technology. Target antigens are screened, in vitro, using phage display libraries having millions to billions of phage particles expressing unique single chain variable fragments (scFvs) on their viral coat. Precipitated phage particles are analyzed and sequences encoding expressed scFvs are determined. Sequences encoding antibody variable domains and/or CDRs are inserted into expression vectors for antibody production.

Recombinant antibodies are further produced using yeast surface display technology, wherein antibody variable domain sequences are expressed on the cell surface of Saccharomyces cerevisiae. Recombinant antibodies are developed by displaying the antibody fragment of interest as a fusion to e.g. Aga2p protein on the surface of the yeast, were the protein interacts with proteins and small molecules in a solution, scFvs with affinity towards desired receptors are isolated from the yeast surface using magnetic separation and flow cytometry. Several cycles of yeast surface display and isolation will be done to attain scFvs with desired properties through directed evolution.

Reverse Translation for Antibody Generation

Nucleotide sequences are derived from antibody amino acid sequences. The amino acid sequence is reverse translated from a parent antibody sequence (e.g., light chain variable or heavy chain variable region) to generate a nucleotide sequence. The nucleotide sequence is then cloned into an antibody constant region framework and tested for expression and activity.

Codon-Optimization

Nucleotide sequences are codon-optimized to enhance one or more desirable features of the encoded antibody (e.g., expression or affinity for the target). Each antibody nucleotide sequence is codon-optimized according to several methods known in the art and compared to the other codon-optimized variants in vitro or in vivo. All codon-optimized variants are then cloned into viral genomes and tested in vitro. The codon-optimized variants with the greatest in vitro or in vivo expression and/or affinity characteristics are selected for further study.

Generation of Antibody Fragments

In addition to generating full length anti-tau antibodies, antibody fragments and variants are also generated. These fragments may lack the effector (Fc) region typically included in a full-length antibody. For each anti-tau antibody (e.g., IPN002, PT3, C10.2, CP13), a series of Fab, F(ab)2 and/or scFv fragments are generated and tested in vitro or in vivo. Those showing the best expression in vitro and/or in vivo are selected for further studies.

Antibody Screening

Anti-tau antibodies that are generated by any of the methods described above or other methods known in the art, are screened for expression and affinity characteristics. Antibodies are screened first with one or more ELISA assays (phospho-tau ELISA, wild-type tau ELISA, or ePHF ELISA). An in vitro cellular screen using a biosensor system is used to assess in vitro seeding. The biosensor system may be a semi-quantitative FRET assay. Further in vitro characterization will be carried out by standard techniques known in the art, such as western blotting or immunoprecipitation, immunohistochemistry, immunocytochemistry, immunofluorescence, or an in vitro seeding assay in primary neurons. Propagation and biophysical characteristics are screened with in vitro and/or in vivo methods, which may rely on a tau-seeding and/or propagation model. Anti-tau antibodies may be purified by any method known to one with skill in the art.

Example 2. Engineering Viral Genomes for the Expression of Anti-Tau Antibodies

Viral genomes were designed for AAV delivery of anti-tau antibodies IPN002, PHF1, MC1, C10.2 or PT3. The ITR to ITR sequences for the viral genomes are given as TAU_ITR1 to TAU_ITR249 as shown in Tables 4-6 and given by SEQ ID NO: 1990-2075 and 2137-2168, 2171-2237 and 2260-2321.

Viral Genomes for the Expression of IPN002

Sixteen viral genomes were generated for delivery of anti-tau antibody IPN002 (TAU_ITR1 to TAU_ITR15 and TAU_ITR87; SEQ ID NO: 1990-2004 and 2137). The payload regions for these viral genomes were designed to comprise an antibody heavy chain signal sequence (SEQ ID NO: 1740), an antibody heavy chain variable region (SEQ ID NO: 1821), an antibody heavy chain constant region (SEQ ID NO: 1742), a linker region, an antibody light chain signal sequence (SEQ ID NO: 1861), an antibody light chain variable region (SEQ ID NO: 1939), and an antibody light chain constant region (SEQ ID NO: 1864), but not always in this order when read 5′ to 3′. The linker region selected for these viral genomes was either T2A (SEQ ID NO: 1726) or F2A (SEQ ID NO: 1727). For TAU_ITR1 to TAU_ITR8 (SEQ ID NO: 1990-1997), a furin cleavage site (SEQ ID NO: 1724 or 1725) was located immediately 5′ to the T2A or F2A linker.

In designing viral genomes for the expression of anti-tau antibody IPN002, one of four promoters were selected. The ubiquitous CAG promoter (SEQ ID NO: 2080), further comprising a CMVie element (SEQ ID NO: 2081) and a CBA minimal promoter region (SEQ ID NO: 2082) was used for TAU_ITR1 (SEQ ID NO: 1990), TAU_ITR2 (SEQ ID NO: 1991), TAU_ITR9 (SEQ ID NO: 1998) and TAU_ITR10 (SEQ ID NO: 1999). The ubiquitous CB promoter (SEQ ID NO: 2083), was used for TAU_ITR3 (SEQ ID NO: 1992), TAU_ITR4 (SEQ ID NO: 1993), TAU_ITR11 (SEQ ID NO: 2000) and TAU_ITR87 (SEQ ID NO: 2137). The astrocyte targeting GFAP promoter (SEQ ID NO: 2085) was used for TAU_ITR5 (SEQ ID NO: 1994), TAU_ITR6 (SEQ ID NO: 1995), TAU_ITR12 (SEQ ID NO: 2001) and TAU_ITR13 (SEQ ID NO: 2002). A neuronal targeting synapsin promoter (SEQ ID NO: 2086) was used for TAU_ITR7 (SEQ ID NO: 1996), TAU_ITR8 (SEQ ID NO: 1997), TAU_ITR14 (SEQ ID NO: 2003) and TAU_ITR15 (SEQ ID NO: 2004).

The viral genomes designed with CB, GFAP and synapsin promoters further included an ie1 exon region (SEQ ID NO: 2090), an ie1 intron 1 region (SEQ ID NO: 2095), a human beta-globin intron region (SEQ ID NO: 2097) and a human beta-globin exon region (SEQ ID NO: 2093). These four elements were always maintained in this order when read 5′ to 3′.

The 5′ ITR (SEQ ID NO: 2076), the polyadenylation sequence (SEQ ID NO: 2122) and the 3′ ITR (SEQ ID NO: 2078) were retained across all sixteen viral genomes designed for the expression of anti-tau antibody IPN002.

The order of heavy and light chains (including signal sequence, variable region and constant region) was alternated with respect to 5′ to 3′ direction. When read 5′ to 3′, viral genomes encoding heavy chain antibody sequences, a linker region, and light chain antibody sequences (heavy-linker-light) include TAU_ITR1 to TAU_ITR8 (SEQ ID NO: 1990-1997). Viral genomes encoding light chain antibody sequences, a linker region, and heavy chain antibody sequences (light-linker-heavy) when read 5′ to 3′, include TAU_ITR9 to TAU_ITR15 (SEQ ID NO: 1998-2004) and TAU_ITR87 (SEQ ID NO: 2137).

In summary, these 16 viral genomes represent four configurations HF.T2AL, HF.F2AL, LT2AH, and LF2AH, each driven by one of four promoters, CAG, CB6, GFAP or synapsin. The description of these viral genomes, including the individual sequence regions, is laid out in Tables 15-20 above.

Viral Genomes for the Expression of C10.2 Codon-Optimized Variants

Ten viral genomes were designed for the expression of anti-tau antibody C10.2 (TAU_ITR16 to TAU_ITR25; SEQ ID NO: 2005-2014). These viral genomes were differentiated from one another by the codon-optimized sequences for C10.2 (with light chain variable regions given by SEQ ID NO: 1921-1930 and heavy chain variable regions given by SEQ ID NO: 1804-1813). Codon-optimization was determined according to one of the following methods: Bioinformatics (TAU_ITR16: SEQ ID NO: 2005), EMBOSS (TAU_ITR17; SEQ ID NO: 2006), GeneInfinity (TAU_ITR18; SEQ ID NO: 2007), Greg Thatcher (TAU_ITR19; SEQ ID NO: 2008), IDT (TAU_ITR20; SEQ ID NO: 2009), In Silico (TAU_ITR21; SEQ ID NO: 2010), Molecular Biology (TAU_ITR22; SEQ ID NO: 2011). N2P (TAU_ITR23; SEQ ID NO: 2012), SnapGene (TAU_ITR24; SEQ ID NO: 2013), or VectorNTI (TAU_ITR25; SEQ ID NO: 2014).

Beyond the antibody light chain variable and heavy chain variable regions, each viral genome included a 5′ ITR (SEQ ID NO: 2076), a CB promoter (SEQ ID NO: 2083), an exon/intron region comprising an ie1 exon 1 region (SEQ ID NO: 2090), an ie1 intron 1 region (SEQ ID NO: 2095), a human beta-globin intron region (SEQ ID NO: 2097) and a human beta-globin exon region (SEQ ID NO: 2093), a light chain antibody signal sequence (SEQ ID NO: 1861), a light chain constant region (SEQ ID NO: 1864), a T2A linker (SEQ ID NO: 1726), a heavy chain signal sequence (SEQ ID NO: 1740), a heavy chain constant region (SEQ ID NO: 1743), a polyadenylation sequence (SEQ ID NO: 2122) and a 3′ ITR (SEQ ID NO: 2078).

Each of these viral genomes was configured in a light-linker-heavy 5′ to 3′ orientation. The description of these viral genomes, including the individual sequence regions, is laid out in Tables 21 and 22 above.

Promoter and Configuration Variants

Sixteen viral genomes, representing four configurations (HF.T2AL, LT2AH, HF.F2AL, LF2AH), driven by each of four promoters (CAG, CBA, GFAP, synapsin) were generated for delivery of anti-tau antibody C10.2 (TAU_ITR21, TAU_ITR88 to TAU_ITR102: SEQ ID NO: 2010, 2138-2152). The payload regions for these viral genomes were designed to comprise an antibody heavy chain (SEQ ID NO: 1809), a linker region (T2A; SEQ ID NO: 1726 or F2A; SEQ ID NO: 1727), and an antibody light chain (SEQ ID NO: 1926), not always in this order when read 5′ to 3′, depending on configuration. C10.2 antibody sequences were codon-optimized according to the InSilico method.

One of four promoters was selected in designing viral genomes for the expression of anti-tau antibody C10.2. The ubiquitous CAG promoter (SEQ ID NO: 2080), further comprising a CMVie element (SEQ ID NO: 2081) and a CBA minimal promoter region (SEQ ID NO: 2082), was used for TAU_ITR89 (SEQ ID NO: 2139), TAU_ITR93 (SEQ ID NO: 2143), TAU_ITR97 (SEQ ID NO: 2147) and TAU_ITR100 (SEQ ID NO: 2150). The ubiquitous CB promoter (SEQ ID NO: 2083), further comprising a CMVie enhancer (SEQ ID NO: 2087) immediately 5′ to the promoter sequence was used for TAU_ITR88 (SEQ ID NO: 2138), TAU_ITR92 (SEQ ID NO: 2142), TAU_ITR96 (SEQ ID NO: 2146) and TAU_ITR21 (SEQ ID NO: 2010). The astrocyte targeting GFAP promoter (SEQ ID NO: 2085) was used for TAU_ITR90 (SEQ ID NO: 2140), TAU_ITR94 (SEQ ID NO: 2144), TAU_ITR98 (SEQ ID NO: 2148) and TAU_ITR101 (SEQ ID NO: 2151). A neuronal targeting synapsin promoter (SEQ ID NO: 2086) was used for TAU_ITR91 (SEQ ID NO: 2141), TAU_ITR95 (SEQ ID NO: 2145). TAU_ITR99 (SEQ ID NO: 2149) and TAU_ITR102 (SEQ ID NO: 2152).

Viral genomes driven by CB, GFAP and synapsin promoters further comprised an intron/exon region consisting of an ie1 exon region (SEQ ID NO: 2090), an ie1 intron region (SEQ ID NO: 2095), a human beta-globin intron region (SEQ ID NO: 2097) and a human beta-globin exon region (SEQ ID NO: 2093), as read in the 5′ to 3′ direction.

The 5′ ITR (SEQ ID NO: 2076), the polyadenylation sequence (SEQ ID NO: 2122), and the 3′ ITR (SEQ ID NO: 2078) were retained across all sixteen viral genomes designed for the expression of anti-tau antibody C10.2.

The order of heavy and light chains was alternated with respect to 5′ to 3′ direction. Eight viral genomes (TAU_ITR88 to TAU_ITR91; SEQ ID NO: 2138-2141 and TAU_ITR96 to TAU_ITR99; SEQ ID NO: 2146-2149) were designed encoding heavy chain antibody sequences, a T2A or F2A linker region, and light chain antibody sequences (heavy-linker-light), when read 5′ to 3′. In these heavy-linker-light configuration viral genomes, the linker also included a furin cleavage site (SEQ ID NO: 1724 or 1725) immediately 5′ to the linker sequence. The other eight viral genomes (TAU_ITR92 to TAU_ITR95; SEQ ID NO: 2142-2145, TAU_ITR21; SEQ ID NO: 2010, and TAU_ITR100 to TAU_ITR102: SEQ ID NO: 2150-2152), when read 5′ to 3′, were designed to encode light chain antibody sequences, a T2A or F2A linker region (linker only, no furin cleavage site), and heavy chain antibody sequences (light-linker-heavy).

In summary, these 16 viral genomes represent four configurations HF.T2AL, LT2AH, HF.F2AL, LF2AH, each driven by one of four promoters CAG, CB. GFAP or synapsin, for the expression of anti-tau antibody C10.2.

Viral Genomes for the Expression of PT3 Codon-Optimized Variants

Ten viral genomes were designed for the expression of anti-tau antibody PT3 (TAU_ITR26 to TAU_ITR35; SEQ ID NO: 2015-2024). These viral genomes were differentiated from one another by the codon-optimized sequences for PT3 (with light chain variable regions given by SEQ ID NO: 1971-1980 and heavy chain variable regions given by SEQ ID NO: 1851-1860). Codon-optimization was determined according to one of the following methods: GeneScript (TAU_ITR26; SEQ ID NO: 2015), SnapGene (TAU_ITR27; SEQ ID NO: 2016). EMBOSS (TAU_ITR28; SEQ ID NO: 2017), Bioinformatics (TAU_ITR29; SEQ ID NO: 2018), NUS (TAU_ITR30; SEQ ID NO: 2019). NUS2 (TAU_ITR31; SEQ ID NO: 2020), GeneInfinity (TAU_ITR32; SEQ ID NO: 2021), IDT (TAU_ITR33; SEQ ID NO: 2022), Bioinformatics2 (TAU_ITR34; SEQ ID NO: 2023), or NUS3 (TAU_ITR35; SEQ ID NO: 2024).

Beyond the antibody light chain variable and heavy chain variable regions, each viral genome included a 5′ ITR (SEQ ID NO: 2077), a CBA promoter (SEQ ID NO: 2084), an exon/intron region comprising an ie1 exon 1 region (SEQ ID NO: 2090), an ie1 intron 1 region (SEQ ID NO: 2095), a human beta-globin intron region (SEQ ID NO: 2097) and a human beta-globin exon region (SEQ ID NO: 2093), a heavy chain antibody signal sequence (SEQ ID NO: 1740), a heavy chain constant region (SEQ ID NO: 1742), a furin cleavage site (SEQ ID NO: 1724), a T2A linker (SEQ ID NO: 1726), a light chain signal sequence (SEQ ID NO: 1861), a light chain constant region (SEQ ID NO: 1864), a polyadenylation sequence (SEQ ID NO: 2123) and a 3′ ITR (SEQ ID NO: 2079). TAU_ITR27 (SEQ ID NO: 2016) had a partial heavy chain antibody signal sequence.

Each of these viral genomes was configured in a heavy-linker-light 5′ to 3′ orientation. The description of these viral genomes, including the individual sequence regions, is laid out in Tables 23 and 24 above.

Nucleotide sequences for the heavy chain and light chains of two codon-optimized variants, encoding anti-tau antibody PT3 were cloned into viral genomes with expression driven by either the CBA or CAG promoters. Four viral genomes were generated, each with an HF.T2AL configuration (TAU_ITR11: SEQ ID NO: 2161, TAU_ITR112; SEQ ID NO: 2162, TAU_ITR119; SEQ ID NO: 2169, TAU_ITR120; SEQ ID NO: 2170). Western blot analysis of PT3 expression from these four viral genome constructs showed the two bands expected to be expressed for each construct tested. Quantification by mouse IgG1 ELISA as a fold change normalized to Lucia indicated enhanced expression using the CAG promoter and the first codon-optimization variant (TAU_ITR120: SEQ ID NO: 2170). Assessment by wild-type tau ELISA showed PT3 binds to wt tau441 at high concentration, while GSK-phosphorylated tau ELISA showed PT3 weakly binds phosphorylated tau441 (GSKed_Tau protein from Signal Chem) and PHF-tau ELISA showed binding patterns of PT3 to PHF-tau substantially similar to those seen with IPN002.

Promoter and Configuration Variants

Sixteen viral genomes, representing four configurations (HF.T2AL, HF.F2AL, LT2AH, and LF2AH), driven by each of four promoters (CAG. CB, GFAP, synapsin) were generated for delivery of anti-tau antibody PT3 (TAU_ITR103 to TAU_ITR120: SEQ ID NO: 2153-2170). The payload regions for these viral genomes were designed to comprise an antibody heavy chain (SEQ ID NO: 1859), a linker region, and an antibody light chain (SEQ ID NO: 1980), not always in this order when read 5′ to 3′, depending on configuration. PT3 antibody sequences were codon-optimized according to the SnapGene codon format. The linker region selected for these viral genomes was either T2A (SEQ ID NO: 1726) or F2A (SEQ ID NO: 1727).

One of four promoters was selected in designing viral genomes for the expression of anti-tau antibody PT3. The ubiquitous CAG promoter (SEQ ID NO: 2080), further comprising a CMVie element (SEQ ID NO: 2081) and a CBA minimal promoter region (SEQ ID NO: 2082) was used for TAU_ITR104 (SEQ ID NO: 2154), TAU_ITR108 (SEQ ID NO: 2158). TAU_ITR116 (SEQ ID NO: 2166) and TAU_ITR112 (SEQ ID NO: 2162). The ubiquitous CB promoter (SEQ ID NO: 2083) was used for TAU_ITR103 (SEQ ID NO: 2153), TAU_ITR107 (SEQ ID NO: 2157), TAU_ITR111 (SEQ ID NO: 2161) and TAU_ITR115 (SEQ ID NO: 2165). The astrocyte targeting GFAP promoter (SEQ ID NO: 2085) was used for TAU_ITR105 (SEQ ID NO: 2155), TAU_ITR109 (SEQ ID NO: 2159), TAU_ITR113 (SEQ ID NO: 2163) and TAU_ITR117 (SEQ ID NO: 2167). A neuronal targeting synapsin promoter (SEQ ID NO: 2086) was used for TAU_ITR106 (SEQ ID NO: 2156), TAU_ITR110 (SEQ ID NO: 2160), TAU_ITR114 (SEQ ID NO: 2164) and TAU_ITR117 (SEQ ID NO: 2167).

The viral genomes designed with CB, GFAP and synapsin promoters further included an ie1 exon region (SEQ ID NO: 2090), an ie1 intron 1 region (SEQ ID NO: 2095), a human beta-globin intron region (SEQ ID NO: 2097) and a human beta-globin exon region (SEQ ID NO: 2093). These four elements were always maintained in this order when read 5′ to 3′.

The 5′ ITR (SEQ ID NO: 2076), the polyadenylation sequence (SEQ ID NO: 2122) and the 3′ ITR (SEQ ID NO: 2078) were retained across all sixteen viral genomes designed for the expression of anti-tau antibody PT3.

The order of heavy and light chains was alternated with respect to 5′ to 3′ direction. Eight viral genomes (TAU_ITR103 to TAU_ITR106; SEQ ID NO: 2153-2156 and TAU_ITR111 to TAU_ITR114: SEQ ID NO: 2161-2164) were designed encoding heavy chain antibody sequences, a linker region, and light chain antibody sequences (heavy-linker-light), when read 5′ to 3′. In these heavy-linker-light configuration viral genomes, the linker also included a furin cleavage site (SEQ ID NO: 1724 or 1725) immediately 5′ to the T2A or F2A linker. The other eight viral genomes (TAU_ITR107 to TAU_ITR110; SEQ ID NO: 2157-2160 and TAU_ITR115 to TAU_ITR118; SEQ ID NO: 2165-2168), when read 5′ to 3′, were designed to encode light chain antibody sequences, a linker region (T2A or F2A only, no furin cleavage site), and heavy chain antibody sequences (light-linker-heavy).

In summary, these 16 viral genomes represent four configurations HF.T2AL, HF.F2AL, LT2AH, and LF2AH, each driven by one of four promoters CAG, CB6, GFAP or synapsin, for the expression of anti-tau antibody PT3.

Viral genomes for the expression of PHF/Thirty-six viral genomes were designed for the expression of anti-tau antibody PHF1 (TAU_ITR36 to TAU_ITR71; SEQ ID NO: 2025-2060).

Either a 130 or 141 nucleotide 5′ ITR (SEQ ID NO: 2076 or 2077, respectively) was selected, and matched with either a 130 or 141 nucleotide 3′ ITR (SEQ ID NO: 2078 or 2079, respectively). TAU_ITR69 to TAU_ITR71 (SEQ ID NO: 2058-2060) included 130 nucleotide ITRs, while TAU_ITR36 to TAU_ITR68 (SEQ ID NO: 2025-2057) included 141 nucleotide ITRs.

Promoters were selected from one of four, (1) CAG promoter (SEQ ID NO: 2080), further comprising a CMVie element (SEQ ID NO: 2081) and a CBA minimal promoter region (SEQ ID NO: 2082), (2) CBA promoter (SEQ ID NO: 2084), (3) CB6 promoter comprising a CMV enhancer (SEQ ID NO: 2087) and a CB promoter (SEQ ID NO: 2083), and (4) GFAP promoter (SEQ ID NO: 2085).

Viral genomes with CBA (TAU_ITR46 to TAU_ITR68: SEQ ID NO: 2035-2057) or CB6 promoters (TAU_ITR69 and TAU_ITR70; SEQ ID NO: 2058 and 2059) were further designed to incorporate an exon/intron region comprising an ie1 exon 1 region (SEQ ID NO: 2090-2092), an ie1 intron 1 region (SEQ ID NO: 2095), a human beta-globin intron region (SEQ ID NO: 2097-2102) and a human beta-globin exon region (SEQ ID NO: 2093), or an SV40 intron (SEQ ID NO: 2103).

At least one signal sequence was incorporated into each viral genome for the expression of PHF1, such as, a light chain antibody signal sequence (SEQ ID NO: 1862), a heavy chain antibody signal sequence (SEQ ID NO: 1741) or a human growth hormone 2 signal sequence (SEQ ID NO: 2106). As many as four signal sequences were incorporated into a single viral genome (TAU_ITR67; SEQ ID NO: 2056).

Nucleotide sequences encoding anti-tau antibody PHF1 were selected from light chain sequences given by SEQ ID NO: 1956, 1957 or 1962, and heavy chain sequences given by SEQ ID NO: 1838 and 1839. As many as 3 pairs of heavy and light chain sequences were incorporated into single viral genomes (TAU_ITR61; SEQ ID NO: 2050, TAU_ITR63; SEQ ID NO: 2052, TAU_ITR65; SEQ ID NO: 2054, TAU_ITR67; SEQ ID NO: 2056). Heavy and light chain antibody sequences were separated by a linker sequence selected from SG4S (encoded by SEQ ID NO: 1729) (corresponding protein sequence disclosed as SEQ ID NO: 4535), G4S3 (encoded by SEQ ID NO: 1730) (corresponding protein sequence disclosed as SEQ ID NO: 4537), F2A (encoded by SEQ ID NO: 1727), T2A (encoded by SEQ ID NP: 1726). In some cases, these linkers were combined with a furin cleavage site given by SEQ ID NO: 1724.

The order of heavy and light chains was alternated with respect to 5′ to 3′ direction (heavy-linker-light vs light-linker-heavy). When read 5′ to 3′, viral genomes in the heavy-linker-light configuration include TAU_ITR36 to TAU_ITR40 (SEQ ID NO: 2025-2029), TAU_ITR46 to TAU_ITR50 (SEQ ID NO: 2035-2039), TAU_ITR56 to TAU_ITR64 (SEQ ID NO: 2045-2053) and TAU_ITR69 (SEQ ID NO: 2058). Viral genomes designed in the light-linker-heavy configuration when read 5′ to 3′, include TAU_ITR41 to TAU_ITR45 (SEQ ID NO: 2030-2034), TAU_ITR51 to TAU_ITR55 (SEQ ID NO: 2040-2044), TAU_ITR65 to TAU_ITR68 (SEQ ID NO: 2054-2057) and TAU_ITR70 (SEQ ID NO: 2059) and TAU_ITR71 (SEQ ID NO: 2060).

One of four tag sequences was selected for use in these viral genomes, with as many as three tags per single viral genome. The tag sequences are given by SEQ ID NO: 2118-2121 and represent HA, SEKDEL (“SEKDEL” disclosed as SEQ ID NO: 4546) (21 nt and 18 nt) and HIS tags, respectively.

Polyadenylation sequences were selected from either a rabbit beta-globin polyadenylation sequence (SEQ ID NO: 2122), or a human growth hormone polyadenylation sequence (SEQ ID NO: 2123).

A subset of these viral genomes were supplemented with an albumin filler sequence selected from SEQ ID NO: 2125 or 2126.

The description of these viral genomes, including the individual sequence regions, is laid out in Tables 25-32 above.

Viral Genomes for the Expression of MC1, PHF1 or IPN002

Viral genomes of Table 6 (SEQ ID NO: 2061-2075; TAU_ITR72-TAU_ITR86) were designed for delivery of anti-tau antibodies MC1 (with heavy chain of SEQ ID NO: 1832 and light chain of SEQ ID NO: 1950), PHF1 (with heavy chain of SEQ ID NO: 1838 and light chain of SEQ ID NO: 1962) and IPN002 (with heavy chain of SEQ ID NO: 1820 and light chain of SEQ ID NO: 1940) to cells. The viral genomes include, besides the antibody coding regions, a 5′ ITR (SEQ ID NO: 2076), a CMV enhancer (SEQ ID NO: 2087), a CB promoter (SEQ ID NO: 2083), an SV40 intron (SEQ ID NO: 2103), a rabbit globin polyadenylation sequence (SEQ ID NO: 2122), and a 3′ITR (SEQ ID NO: 2078).

Viral genomes were designed to encode a linker between light and heavy chain antibody sequences. Linker sequences were derived from an internal ribosome entry site (IRES; SEQ ID NO: 1732), foot and mouth disease virus 2A (F2A; SEQ ID NO: 1727), porcine teschovirus-1 virus 2A (P2A; SEQ ID NO: 1728), or G4S5 (SEQ ID NO: 1731) (corresponding protein sequence disclosed as SEQ ID NO: 4538) sequences. For TAU_ITR72 (SEQ ID NO: 2061), TAU_ITR73 (SEQ ID NO: 2062), TAU_ITR77 (SEQ ID NO: 2066), TAU_ITR78 (SEQ ID NO: 2067), TAU_ITR83 (SEQ ID NO: 2072) and TAU_ITR85 (SEQ ID NO: 2074), a furin cleavage site (F: SEQ ID NO: 1725) was introduced immediately 5′ to the linker sequence. The order of heavy and light chains was alternated with respect to 5′ to 3′ direction. When read 5′ to 3′, viral genomes encoding a heavy chain antibody sequence, a linker region, and a light chain antibody sequence (heavy-linker-light) include TAU_ITR72 to TAU_ITR77 (SEQ ID NO: 2061-2066) and TAU_ITR85 (SEQ ID NO: 2074). Viral genomes encoding a light chain antibody sequence, a linker region, and a heavy chain antibody sequence (light-linker-heavy) when read 5′ to 3′, include TAU_ITR78 to TAU_ITR84 (SEQ ID NO: 2067-2073) and TAU_ITR86 (SEQ ID NO: 2075).

The description of these viral genomes, including the individual sequence regions, is laid out in Tables 33-36 above.

The viral genomes for expression of IPN002, C10.2, PT2, PHF1 and MC1 were incorporated into AAV particles using an AAV1, AAV2, or VOY101 capsid.

Example 3. Production and Purification of AAV Particles

Any of the viral genomes described herein (e.g., those of Example 2) may be encapsulated in an AAV capsid to generate an AAV particle. AAV particles described herein may be produced using methods known in the art, such as, for example, triple transfection or baculovirus mediated virus production. Any suitable permissive or packaging cell known in the art may be employed to produce the particles. Mammalian cells are often preferred. Also preferred are trans-complementing packaging cell lines that provide functions deleted from a replication-defective helper virus, e.g., 293 cells or other Ela trans-complementing cells.

The gene cassette may contain some or all of the parvovirus (e.g., AAV) cap and rep genes. Preferably, however, some or all of the cap and rep functions are provided in trans by introducing a packaging vector(s) encoding the capsid and/or Rep proteins into the cell. Most preferably, the gene cassette does not encode the capsid or Rep proteins. Alternatively, a packaging cell line is used that is stably transformed to express the cap and/or rep genes

Recombinant AAV virus particles are, in some cases, produced and purified from culture supernatants according to the procedure as described in US20160032254, the contents of which are incorporated by reference. Production may also involve methods known in the art including those using 293T cells, sf9 insect cells, triple transfection or any suitable production method.

In some cases, 293T cells (adhesion/suspension) are transfected with polyethyleneimine (PEI) with plasmids required for production of AAV, i.e., AAV2 rep, an adenoviral helper construct and an ITR flanked transgene cassette. The AAV2 rep plasmid also contains the cap sequence of the particular virus being studied. Twenty-four hours after transfection (no medium changes for suspension), which occurs in DMEM/F17 with/without serum, the medium is replaced with fresh medium with or without serum. Three (3) days after transfection, a sample is taken from the culture medium of the 293 adherent cells. Subsequently cells are scraped, or suspension cells are pelleted, and transferred into a receptacle. For adhesion cells, after centrifugation to remove cellular pellet, a second sample is taken from the supernatant after scraping. Next, cell lysis is achieved by three consecutive freeze-thaw cycles (−80 C to 37 C) or adding detergent triton. Cellular debris is removed by centrifugation or depth filtration and sample 3 is taken from the medium. The samples are quantified for AAV particles by DNase resistant genome titration by DNA qPCR. The total production yield from such a transfection is equal to the particle concentration from sample 3 described above.

AAV particle titers are measured according to genome copy number (genome particles per milliliter). Genome particle concentrations are based on DNA qPCR of the vector DNA as previously reported (Clark et al. (1999) Hum. Gene Ther., 10:1031-1039; Veldwijk et al. (2002) Mol. Ther., 6:272-278).

Example 4. Development of ELISA Assay to Determine Affinity to ePHF Tau

An assay was developed to determine the affinity of anti-tau antibodies, expressed from various viral genome constructs, for extracellular tau in the form of paired helical filaments (ePHF). The ePHF were first immobilized on a 96-well plate overnight by pre-coating with 1500× of the concentrated PHF tau at 4° C., washed 3 times with PBS then blocked with 3% BSA for 2 hrs at room temperature or overnight at 4° C. Supernatants from suspensions of Expi 293 cells transfected with anti-tau antibody viral genome constructs (TAU_ITR72-TAU_ITR86) were collected and loaded onto the plates. Anti-tau antibody MC1 was diluted in 3% BSA and analyzed separately as a control. Plates were then incubated for 2 hrs at room temperature. Wells were washed 5 times with TBS/0.5% Tween 20 wash buffer, then incubated with 1:5000 dilution of anti-mouse antibody labeled with HRP (Thermo Fisher Scientific, Waltham, Mass.) for 30 min. Plates were then developed by incubating with one-step TMB substrate (Thermo Fisher Scientific, Waltham, Mass.) for 30 min, stopped by 2N H₂SO₄ and read using a BioTek Synergy H1 hybrid reader (BioTek, Winooski, Vt.) at 450 nm. The concentration of anti-tau antibodies, and their affinity for ePHF tau, was determined using a standard curve. Anti-tau antibodies produced using MC1LIRESH (TAU_ITR80), MC1LF2AH (TAU_ITR79), MC1HF.F2AL (TAU_ITR72), MC1LF.F2AH (TAU_ITR78), and MC1HF.P2AL (TAU_ITR73) viral genome constructs showed similar affinity for ePHF tau as the MC1 control. Anti-tau antibodies generated using MC1HIRESL (TAU_ITR75), MC1LP2AH (TAU_ITR82) and MC1LF.P2AH (TAU_ITR83) viral genome constructs demonstrated lower affinity to ePHF tau than control MC1. Data are shown in Table 92 below (construct names are shown without the MC1 prefix).

TABLE 92 ePHF Tau ELISA: OD450 data ng/ml HIRESL LIRESH LF2AH HF.F2AL LF.F2AH LP2AH HFP2AL LF.P2AH MC1 1000.0 1.0 1.0 1.1 1.1 1.1 0.8 0.9 0.6 — 500.0 0.7 0.9 1.0 1.0 1.0 0.7 0.9 0.4 — 166.7 0.3 0.6 0.7 0.7 0.7 0.4 0.6 0.2 — 55.6 0.2 0.3 0.4 0.5 0.4 0.2 0.4 0.1 — 18.5 0.1 0.2 0.2 0.3 0.2 0.1 0.2 0.1 — 6.2 0.1 0.1 0.1 0.2 0.1 0.1 0.1 0.1 — 2.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 — 0.7 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 — 2558.9 — — — — — — — — 1.2 1279.4 — — — — — — — — 1.2 426.5 — — — — — — — — 1.0 142.2 — — — — — — — — 0.7 47.4 — — — — — — — — 0.4 15.8 — — — — — — — — 0.2 5.3 — — — — — — — — 0.3 1.8 — — — — — — — — 0.1

According to the same assay, MC1LF2AH (TAU_ITR79), MC1HF.F2AL (TAU_ITR72), IPN002LF2AH (TAU_ITR84), IPN002HF.F2AL (TAU_ITR77), PHF-1LF2AH (TAU_ITR86), and PHF-1HF.F2AL (TAU_ITR85) viral genome constructs were expressed in Expi 293 cells, the supernatants collected and expressed antibodies were tested for affinity to ePHF tau. Antibodies generated from the six viral genome constructs tested showed similar affinity for ePHF tau in comparison to their respective control antibodies (MC1. PHF1 and IPN002 antibodies).

Example 5. ELISA Assay for Detection of Expressed Antibodies

Expi 293 cell culture supernatants from cells expressing anti-tau antibodies were tested by sandwich ELISA to detect and determine concentrations of expressed antibodies. Ninety-six well plates were pre-coated with anti-mouse IgG1 overnight at 4° C. then washed 3 times with PBS and blocked with 3% BSA for 2 hrs at room temperature. Supernatants were diluted in blocking buffer (3% BSA), added to the wells and incubated for 2 hrs at room temperature. Samples were then washed 5 times with TBS/0.5% Tween 20 wash buffer and incubated with 1:5000 dilution of anti-mouse antibody labeled with HRP (Thermo Fisher Scientific, Waltham, Mass.) for 30 min. Plates were developed by incubating with one-step TMB substrate for 30 min, stopped by 2N H₂SO₄ and read using a BioTek Synergy H1 hybrid reader (BioTek, Winooski, Vt.) at 450 nm. The concentration of expressed MC1 anti-tau antibodies was then determined for each construct using a standard curve (see Table 93).

TABLE 93 Concentrations of expressed antibodies Construct name Antibody concentration μg/ml MC1HIRESL 4.42 MC1LIRESH 32.29 MC1LF2AH 10.74 MC1HF.F2AL 12.10 MC1LF.F2AH 12.94 MC1LP2AH 44.12 MC1HF.P2AL 23.79 MC1LF.P2AH 46.43

Cells expressing MC1LIRESH (TAU_ITR80), MC1LP2AH (TAU_ITR82) and MC1LF.P2AH (TAU_ITR83) viral genome constructs produced the highest concentration of antibodies from transfected cells.

In a subsequent experiment using the same methods, cell supernatants from Expi 293 cells expressing MC1LF2AH (TAU_ITR79), MC1HF.F2AL (TAU_ITR72), PHF1LF2AH (TAU_ITR86), PHF1HF.F2AL (TAU_ITR85), IPN002LF2AH (TAU_ITR84), or IPN002HF.F2AL (TAU_ITR77) viral genome constructs were also assessed for concentrations of expressed antibodies by sandwich ELISA. Antibody concentrations from supernatants tested are presented in Table 94.

TABLE 94 Concentrations of expressed antibodies Construct name Antibody concentration μg/ml MC1LF2AH 40.4 MC1HF.F2AL 4.5 PHF1LF2AH 28.3 PHF1HF.F2AL 2.9 IPN002LF2AH 10.2 IPN002HF.F2AL 1.6

Cells expressing MC1LF2AH (TAU_ITR79), PHF1LF2AH (TAU_ITR86) and IPN002LF2AH (TAU_ITR84) viral genome constructs produced the highest concentration of antibodies from transfected cells.

Example 6. Western Blotting for Anti-Tau Antibody Expression

Anti-tau antibodies expressed using MC1HIRESL (TAU_ITR75), MC1LIRESH (TAU_ITR80), MC1HF2AL (TAU_ITR74), MC1LF2AH (TAU_ITR79), MC1HF.F2AL (TAU_ITR72), MC1LF.F2AH (TAU_ITR78), MC1HP2AL (TAU_ITR76), MC1LP2AH (TAU_ITR82), MC1HF.P2AL (TAU_ITR73), MC1LF.P2AH (TAU_ITR83), and MC1LG4S5H (TAU_ITR81) viral genome constructs were assessed by Western blotting in both small and large volume (30 mL) cell culture experiments. Expi 293 cells expressing MC1HIRESL (TAU_ITR75), MC1LIRESH (TAU_ITR80), MC1 HF2AL (TAU_ITR74), MC1LF2AH (TAU_ITR79), MC1HF.F2AL (TAU_ITR72). MC1LF.F2AH (TAU_ITR78), MC1HP2AL (TAU_ITR76), MC1LP2AH (TAU_ITR82), MC1HF.P2AL (TAU_ITR73). MC1LF.P2AH (TAU_ITR83), and MC1LG4S5H (TAU_ITR81) viral genome constructs were cultured to produce antibody-rich supernatant. After centrifugation, supernatants were collected and two small samples of each were removed and mixed with equal volumes of Laemmli sample buffer. Samples were then boiled at 95° C. for 5 min before loading into two 4-20% polyacrylamide gels along with molecular weight markers. Both gels were run for 1-2 hrs at 100V under reducing or non-reducing conditions. Proteins were then transferred to a nitrocellulose membrane for 2 hr at 4° C. and stained with anti-mouse IgGs. First, membranes were placed in blocking buffer for 1 h at room temperature or overnight at 4° C. followed by incubation with anti-mouse IgG antibodies in blocking buffer overnight at 4° C. The membranes were then washed three times each for 5 min in TBST and incubated with enzyme-labeled secondary antibody in blocking buffer for 1 hr at room temperature. Membranes were washed three times each for 5 min in TBST then developed using a luminescent substrate.

Under both reducing and non-reducing conditions, three viral genome constructs showed limited expression when initially assessed by Western blot. In normal (reducing) conditions, antibody heavy chains usually run at approximately 50 kD, while light chains are evident at 25 kD. In supernatant from cells expressing MC1HF2AL (TAU_ITR74) and MC1LG4S5H (TAU_ITR81) viral genome constructs, only the 25 kD species was evident while in supernatant from cells expressing MC1HP2AL (TAU_ITR76), neither species appeared. The remaining supernatants showed the anticipated 25 and 50 kD species under reducing conditions and several high molecular weight (80-150 kD) bands under non-reducing conditions.

A similar experiment was conducted using MC1LF2AH (TAU_ITR79), MC1HF.F2AL (TAU_ITR72), IPN002LF2AH (TAU_ITR84), IPN002HF.F2AL (TAU_ITR77), PHF-1LF2AH (TAU_ITR86), and PHF-1HF.F2AL (TAU_ITR86) viral genome constructs. Western blot showed the expected 25 kD and 50 kD bands under reducing conditions and high molecular weight triplets under non-reducing conditions, similar to the appropriate controls (MC1, PHF1 and IPN002 antibodies). LF2AH viral genome constructs generated better expression levels for all three antibodies than the HF.F2AL viral genome constructs.

Antibody concentrations from scaled-up culture conditions (30 mL) were determined for select constructs (see Table 95).

TABLE 95 Antibody concentrations from 30 mL cultures Construct name Concentration μg/ml MC1LIRESH 20.3 MC1LF2AH 86.2 MC1HF.F2AL 9.9 MC1LF.F2AH 14.7 MC1HF.P2AL 15.9

Viral genome construct MC1 LF2AH (TAU_ITR79) yielded the highest concentration of antibody from transfected cells.

Example 7. Purification of Anti-Tau Antibody Constructs Purification of Anti-Tau Antibody MC1

Anti-tau antibodies expressed in large volumes of Expi 293 cells (30 mL) were purified using protein A/G beads. A column was prepared with protein A/G bead resin and washed 3 times with loading buffer. Supernatants were diluted with equal volumes of loading buffer and applied to the column. Unbound proteins were washed through with loading buffer. Elution buffer was added to the column and fractions collected. Fractions containing proteins were identified by absorbance at 280 nm, pooled together, neutralized and run on polyacrylamide gels as described in Example 6. Under reducing conditions, antibodies produced using MC1LIRESH (TAU_ITR80), MC1LF2AH (TAU_ITR79), MC1HF.F2AL (TAU_ITR72), MC1LF.F2AH (TAU_ITR78), and MC1HF.P2AL (TAU_ITR73) viral genome constructs yielded protein bands when examined by Western blotting that were similar to those observed with MC1 control antibody (bands at 25 kD and 50 kD). Under non-reducing conditions, all expressed antibodies generated a triplet set of bands between 80-150 kD, as did the MC1 control.

Purified anti-tau antibodies were then tested for their affinity to ePHF tau by ELISA assay as described in Example 4. Antibodies with the highest affinity for ePHF tau were those produced using MC1LF2AH (TAU_ITR79), MC1HF.F2AL (TAU_ITR72) and MC1LF.F2AH (TAU_ITR78) viral genome constructs. These antibodies all demonstrated affinity for ePHF tau that was similar to that observed with MC1 control antibody.

Purification of anti-tau antibody PT3 Anti-tau antibody PT3 was produced and purified in a IL culture of ExpiCHO cells, as described above. Cells were transfected with expifectamine and maintained in culture. The culture media was harvested and PT3 purified using a Protein G column, then concentrated to 6 mg/ml in 1×PBS with 55 mM NaCl and 0.001% F-68. When examined by SDS-PAGE under reduced conditions, bands at approximately 25 kD and 50 kD were observed. Under non-reducing conditions, bands were evident at approximately 160 kD. The purified PT3 antibody was tested for affinity to ePHF and wild-type tau by ELISA assay and demonstrated a greater affinity for ePHF tau.

Example 8. Optimization of Viral Genomes for Antibody Expression Viral Genomes for IPN002 Antibody Expression

Ten viral genomes (TAU_ITR1 to TAU_ITR4, TAU_ITR9 to TAU_ITR11, TAU_ITR87, TAU_ITR84, and TAU_ITR77) were generated to test the influence of ubiquitous promoters (CB6 vs CAG) and configuration (HF.F2AL vs LF2AH) on IPN002 expression. Characterization included ExpiCHO transfection, mouse IgG1 ELISA, Western blot, Phospho-tau ELISA and wild-type tau ELISA.

ExpiCHO cells were transfected with each of the IPN002 antibody expressing viral genome constructs listed above to generate an antibody-rich supernatant. Samples of supernatant were prepared for analysis by mouse IgG1 ELISA to determine the expression level of anti-tau antibody IPN002 in the ExpiCHO cells. Quantification of IgG1 (μg/mL) and the average fold change when normalized to Lucia, is shown in Table 96 below.

TABLE 96 Quantification of ExpiCHO Transfection with IPN002 constructs SEQ Norm. Avg. TAU_ITR ID IgG1 to Fold Fold Construct Name ID NO: Lucia (μg/mL) Lucia Change Change CB6-IPN002-HF.F2AL TAU_ ITR3 1992 11503.8 4.9 0.4 2.8 2.8 11224.7 4.8 0.4 2.8 CAG-IPN002-HF.F2AL TAU_ITR2 1991 5859.2 5.0 0.9 5.5 5.5 6533.7 5.5 0.8 5.5 CB6-IPN002-LF2AH TAU_ITR11 2000 11627.9 15.4 1.3 8.5 7.8 18215.9 20.0 1.1 7.0 CAG-IPN002-LF2AH TAU_ITR9 1998 10953.3 52.3 4.8 30.1 46.9 3238.4 31.8 9.8 63.1 CB6-IPN002-HF.T2AL TAU_ITR4 1993 18660.5 23.6 1.3 8.1 5.8 15305.7 8.3 0.5 3.5 CAG-IPN002-HF.T2AL TAU_ITR1 1990 13201.9 74.4 5.6 36.2 32.7 9462.1 42.9 4.5 29.1 CB6-IPN002-LT2AH TAU_ITR87 2137 9198.4 58.0 6.3 40.5 31.6 17042.6 60.5 3.5 22.8 CAG-IPN002-LT2AH TAU_ITR10 1999 16716.9 90.6 5.4 34.8 36.2 14401.1 84.4 5.9 37.6 CB6-SV40-IPN002-LF2AH TAU_ITR84 2073 15274.7 8.0 0.5 3.4 3.4 CB6-SV40-IPN002-HF.F2AL TAU_ITR77 2066 18471.8 2.9 0.2 1 1

Samples of supernatant were prepared for analysis by Western blot, as described in Example 6 above. The resultant Western blots were reviewed for the presence of heavy (50 kD) and light chain (25 kD) species, which were evident for all constructs tested.

Two ELISA assays (PHF-1 IgG1 and anti-eTau), as described in Examples 4 and 5, were also performed to determine antibody production from eight of the constructs. Results are shown in Table 97 below. Cell-free supernatant and anti-tau antibody IPN002 were used as negative and positive controls, respectively.

TABLE 97 ELISA for analysis of antibody production TAU_ITR SEQ PHF-1 IgG1 anti-eTau Construct Name ID ID NO: ELISA: ng/ml ELISA: ng/ml CB6-IPN002-HF.F2AL TAU_ITR3 1992 9.9 6.8 CAG-IPN002-HF.F2AL TAU_ITR2 1991 9.3 7.0 CB6-IPN002-LF2AH TAU_ITR11 2000 12.4 8.8 CAG-IPN002-LF2AH TAU_ITR9 1998 14.9 10.8 CB6-IPN002-HF.T2AL TAU_ITR4 1993 12.4 9.0 CAG-IPN002-HF.T2AL TAU_ITR1 1990 18.4 12.8 CB6-IPN002-LT2AH TAU_ITR87 2137 21.5 14.6 CAG-IPN002-LT2AH TAU_ITR10 1999 19.6 13.4 Ctl supernatant — — 0 0 IPN002 ctl — — 16.2 14.7

The anti-tau antibody IPN002 expressed from these viral genome constructs binds both phospho- and wild-type tau, based on ELISA.

VOY101.IPN002 Promoter and Viral Genome Configuration Studies in Rodents

Four viral genome configurations (HF.T2AL, HF.F2AL, LT2AH, and LF2AH) for the expression of anti-tau antibody IPN002 were matched with each of four promoters (CAG, CB6, GFAP and synapsin), for the generation of 16 viral genome variants as described in Example 2 and outlined in Tables 15-20. To determine the effects of the promoters and viral genome configurations on brain distribution, cellular tropism, and expression levels, the viral genomes were packaged in VOY101 capsids and single stranded AAV particles delivered by intravenous administration to mice.

First, two intravenous administration routes and associated pharmacokinetics were compared using TAU_ITR1 (SEQ ID NO: 1990) packaged in VOY101 delivered to mice. Overall, the pharmacokinetics and biodistribution patterns were substantially similar if ssAAV particles were delivered via tail vein or retro-orbitally. For the purposes of the present disclosure, when animal studies are described, the term intravenous delivery may refer to any means of intravenous delivery, including, but not limited to, tail vein injection or retro-orbital injection.

Ubiquitous Promoters for IPN002 Expression

First, viral genomes TAU_ITR1 (SEQ ID NO: 1990; CAG-HF.T2AL), TAU_ITR10 (SEQ ID NO: 1999; CAG-LT2AH), TAU_ITR4 (SEQ ID NO: 1993; CB6-HF.T2AL), and TAU_ITR87 (SEQ ID NO: 2137; CB6-LT2AH), utilizing ubiquitous CAG or CB6 promoters and HF.T2AL or LT2AH configurations were assessed. These four viral genomes were packaged into VOY101 AAV particles (single stranded) and formulated in PBS and 0.001% F-68. Vehicle PBS with 0.001% F-68 was used as a control. An intravenous bolus at a dose of 1.4×1013 vg/kg was administered via tail vein to two-month old female C57Bl/6 mice (n=4 per group; 20 total mice). Twenty-eight days later, mice were sacrificed by intracardiac perfusion and tissue samples collected from the olfactory bulb, hippocampus, cortex, thalamus, brain stem, spinal cord, spleen, liver, and skeletal muscle and processed for further analysis. Serum samples were collected daily. The study design is shown in Table 98 below.

TABLE 98 ssVOY101.IPN002 CAG/CB6 promoter study design SEQ End Construct TAU_ITR ID Dose Dose of Configuration ID NO: μL (vg/kg) (vg) Route N study CAG-IPN002-HF.T2AL TAU_ITR1 1990 100 1.4E13 2.8E11 IV 4 D 28 CAG-IPN002-LT2AH TAU_ITR10 1999 100 1.4E13 2.8E11 IV 4 D 28 CB6-IPN002-HF.T2AL TAU_ITR4 1993 100 1.4E13 2.8E11 IV 4 D 28 CB6-IPN002-LT2AH TAU_ITR87 2137 100 1.4E13 2.8E11 IV 4 D 28 PBS with 0.001% F-68 — — 100 — — IV 4 D 28

Samples were analyzed by ePHF ELISA or total tau ELISA, immunohistochemistry (NeuN, GFAP, Iba) and/or immunofluorescence or hematoxylin and eosin staining (H&E) and vector genome quantification using droplet digital PCR (ddPCR) normalized to diploid cell number (VG/DC) using the endogenous transferrin receptor gene (TFRC). Secondary readouts included daily cage side observations for 1 week after AAV particle administration and weekly body weight measurements. Steady increases in body weight over the course of the study indicated that no obvious health issues were encountered as a result of treatment. Vector genome quantifications (VG/DC are shown in Table 99 below.

TABLE 99 Vector genome quantification of ssVOY101.IPN002 constructs TAU_ITR1 TAU_ITR10 TAU_ITR4 TAU_ITR87 Vehicle (CAG-HL) (CAG-LH) (CB-HL) (CB-LH) (PBS) Hippocampus 5.0 8.1 8.7 15.3 0.0 Cortex 7.2 14.0 19.4 42.2 0.0 Olfactory Bulb 2.4 5.2 7.6 17.6 0.0 Thalamus 7.9 13.9 20.4 35.7 0.0 Brainstem 8.1 14.7 21.8 36.6 0.0 Spinal Cord 4.9 8.0 12.6 24.8 0.0 Liver 0.5 0.9 2.0 3.1 0.0 Skeletal Muscle 0.1 0.2 0.5 1.7 0.0 Spleen 0.4 0.4 1.2 2.5 0.0

In all tissues analyzed, including CNS tissues (hippocampus, cortex, olfactory bulb, thalamus, brainstem and spinal cord), TAU_ITR87 (SEQ ID NO: 2137) with configuration CB6-IPN002-LT2AH showed the highest vector genome quantification per diploid cell. One mouse from this group demonstrated significantly low AAV biodistribution and transduction and these data were removed from the analysis. In peripheral tissues (liver, skeletal muscle and spleen), quantification of vector genome distribution per cell was low for each of the 4 constructs tested. Intravenous administration of ssVOY101.IPN002 particles resulted in markedly higher CNS tissue biodistribution, as compared to in peripheral tissues. Higher vector genome levels were detected when driven by the CB6 promoter as opposed to the CAG promoter.

Samples of hippocampus, cortex, olfactory bulb, thalamus, brainstem, spinal cord, liver and serum were subjected to analysis by ePHF ELISA to determine IPN002 expression from each of the four IPN002 viral genomes tested. IPN002 antibody expression was then normalized to the viral genome biodistribution (IPN002/VG). Data are shown in Table 100 below as ng/mg protein (or ng/mL for serum samples) and IPN002/vg (shortened to ab/vg). Data for one mouse were omitted since no vector genomes were detected.

TABLE 100 IPN002 expression from ssVOY101.IPN002 constructs (ng/mg protein or mL) TAU_ITR1 TAU_ITR10 TAU_ITR4 TAU_ITR87 Vehicle (CAG-HL) (CAG-LH) (CB-HL) (CB-LH) (PBS) ng/mg ab/vg ng/mg ab/vg ng/mg ab/vg ng/mg ab/vg ng/mg ab/vg Hippocampus 62.7 9.7 48.0 6.6 35.9 3.8 44.2 2.9 0.0 0.0 Cortex 106.1 12.4 62.3 4.6 54.8 2.6 22.3 0.6 0.0 0.0 Olfactory Bulb 72.6 23.1 44.2 9.3 35.3 5.9 27.5 1.6 0.0 0.0 Thalamus 59.0 6.6 46.7 3.3 40.1 1.8 16.0 0.4 0.0 0.0 Brainstem 138.5 14.9 126.8 11.1 111.9 5.4 60.5 1.7 0.0 0.0 Spinal Cord 124.3 24.3 150.3 28.6 78.7 4.6 34.0 1.4 0.0 0.0 Liver 39.5 81.0 118.2 175.9 8.9 5.5 5.7 2.1 0.0 0.0 Serum (ng/mL) 3295.6 — 16209 — 4807.6 — 3364.5 — 0.0 0.0

None of the four viral genomes was proven to significantly enhance IPN002 antibody expression, though TAU_ITR4 (SEQ ID NO: 1993; CB6-IPN002-HF.T2AL) showed a trend toward increased IPN002 expression, as compared to expression from the other three viral genomes. Based on IPN002 expression normalized to vector genome data, TAU_ITR1 (SEQ ID NO: 1990; CAG-IPN002-HF.T2AL) showed the highest expression per vector genome.

Immunofluorescent IgG staining of brain tissue collected from mice treated with an IV injection of ssVOY101.IPN002 AAV particles comprising viral genomes encoding IPN002, driven by CAG or CB6 promoters and one of two viral genome configurations (HF.T2AL or LT2AH). showed greater immunofluorescence (i.e., antibody penetration) in tissue of mice treated with heavy-linker-light chain configuration, as compared to light-heavy-linker configuration with the use of both CAG and CB6 promoters. Comparisons of antibody expression from viral genomes with the same genome configurations but different promoters indicated that the CAG promoter drove higher expression in brain tissues, as measured by immunofluorescence. The highest immunofluorescent signal was observed with TAU_ITR1 (SEQ ID NO: 1990: CAG-IPN002-HF.T2AL), which was consistent with the ePHF tau ELISA results.

Co-immunostaining (fluorescent) of brain tissues for IPN002 (IgG) and neuronal (NeuN) or astrocytic (GFAP) markers showed co-localization of IPN002 with NeuN in neurons of the hippocampus, cortex and thalamus, as well as with GFAP in astrocytes of the cortex.

Anti-IgG immunohistochemistry of brain tissue collected from mice 28 days after treatment with an IV bolus injection of ssVOY101.IPN002 AAV particles comprising viral genomes encoding IPN002, driven by CAG or CB6 promoters and one of two viral genome configurations (HF.T2AL or LT2AH), showed broad antibody expression across the mouse CNS, but stronger staining in tissue of mice treated with heavy-linker-light chain configuration, as compared to light-heavy-linker configuration with the use of both CAG and CB6 promoters. Vehicle-treated control animals exhibited low background levels of staining. Expression of IPN002 antibody was observed in a non-cell type specific manner (neurons and astrocytes showed staining) across multiple brain regions, as may be expected when using ubiquitous promoters.

Immunohistochemistry of brain tissue of mice, treated with an IV bolus injection of ssVOY101.IPN002 AAV particles comprising viral genomes encoding IPN002, driven by CAG or CB6 promoters 28 days prior, for IPN002 (IgG) and astrocytic (S100β) markers showed co-localization of IPN002 with S100β positive cells.

Together, these data indicate that CAG and CB6 promoters may be used to effectively drive IPN002 expression in brain tissue of mice. Viral genome configuration heavy-linker-light leads to approximately 2-fold greater IPN002 antibody expression and tissue distribution, as compared to the light-linker-heavy viral genome configuration, regardless of whether the CAG or CB6 promoter is used. When CAG and CB6 promoters were compared, the CAG promoter was observed to drive greater expression of IPN002 as compared to CB6, regardless of the viral genome configuration. The highest expression of IPN002, per vector genome, was observed from TAU_ITR1 (SEQ ID NO: 1990; CAG-IPN002-HF.T2AL).

Ubiquitous Promoters and T2A or F2A Linkers for IPN002 Expression

In a second study, the effect of using ubiquitous CAG or CB6 promoters for driving expression of IPN002 from two different viral genome configurations (HF.F2AL or LF2AH) was assessed based on measurement of brain distribution, cellular tropism and antibody expression level. Data from this study further enabled comparison of the effects of T2A and F2A cleavage sites on IPN002 antibody expression, distribution and tropism.

Viral genomes TAU_ITR2 (SEQ ID NO: 1991; CAG-HF.F2AL), TAU_ITR9 (SEQ ID NO: 1998: CAG-LF2AH), TAU_ITR3 (SEQ ID NO: 1992; CB6-HF.F2AL), and TAU_ITR11 (SEQ ID NO: 2000; CB6-LF2AH), were packaged, single stranded, into VOY101 AAV particles an, formulated in PBS and 0.001% F-68. Vehicle PBS with 0.001% F-68 was used as a control. An intravenous bolus at a dose of 1.4×10¹³ vg/kg was administered via tail vein to two-month old female C57Bl/6 mice (n=4 per group; 20 total mice). Twenty-eight days later, mice were sacrificed by intracardiac perfusion and tissue samples collected and processed for further analysis. The right half of the brain (including olfactory bulb) and lumbar spinal cord were post-fixed with 4% PFA for immunohistochemistry. The other half of the brain (dissected into hippocampus, cortex, thalamus, brainstem) and cervical and thoracic spinal cord tissues were processed for use in ELISA assays and vector genome quantification by droplet digital PCR normalized to diploid cell number (VG/DC) using the endogenous transferrin receptor gene (TFRC). Peripheral tissues from spleen, liver and skeletal muscle were also collected. Serum samples were collected at two days prior to dosing, and weekly after dosing on days 7, 14, 21 and 28 (terminal day). CSF samples were collected on the terminal day (D28). The study design is shown in Table 101 below.

TABLE 101 ssVOY101.IPN002 CAG/CB6 promoter and linker study design SEQ End Construct TAU_ITR ID Dose Dose of Configuration ID NO: μL (vg/kg) (vg) Route N study CAG-HF.F2AL TAU_ITR2 1991 100 1.4E13 2.8E11 IV 4 D 28 CAG-LF2AH TAU_ITR9 1998 100 1.4E13 2.8E11 IV 4 D 28 CB6-HF.F2AL TAU_ITR3 1992 100 1.4E13 2.8E11 IV 4 D 28 CB6-LF2AH TAU_ITR11 2000 100 1.4E13 2.8E11 IV 4 D 28 PBS with 0.001% F-68 — — 100 — — IV 4 D 28

CNS, peripheral and serum samples were analyzed by ePHF ELISA. Brain, olfactory bulb and spinal cord tissues were assessed by immunohistochemistry (NeuN, S100β, IgG), immunofluorescence and/or hematoxylin and eosin staining (H&E). Vector genome quantification using droplet digital PCR (ddPCR) was carried out for samples collected from cortex, hippocampus, anterior olfactory bulb, brain stem, thoracic spinal cord, liver and skeletal muscle. Secondary readouts included daily cage side observations for 1 week after AAV particle administration and weekly body weight measurements. Steady increases in body weight over the course of the study indicated that no obvious health issues were encountered as a result of treatment. Vector genome quantifications (VG/DC) are shown in the Table 102 below.

TABLE 102 Vector genome quantification of ssVOY101.IPN002 constructs TAU_ITR2 TAU_ITR9 TAU_ITR3 TAU_ITR11 Vehicle (CAG-HL) (CAG-LH) (CB6-HL) CB6-LH) (PBS) Hippocampus 7.0 7.3 17.2 16.8 0.0 Cortex 17.4 13.8 23.5 36.0 0.0 Olfactory Bulb 7.1 6.9 10.0 12.5 0.1 Thalamus 20.3 18.2 34.0 42.2 0.0 Brainstem 20.5 19.9 24.8 44.2 0.1 Spinal Cord 11.1 9.5 16.0 26.3 0.2 Liver 5.6 2.0 6.8 5.9 0.0 Skeletal Muscle 0.4 0.4 0.7 1.5 0.0 Spleen 1.7 1.6 4.3 4.2 0.1

Across the six CNS tissues analyzed, treatment with each of the four viral genome configurations resulted in similar AAV biodistribution, with no statistically significant difference between treatment groups. A trend was seen toward higher AAV genomes per cell in animals treated with CB6 promoter constructs. In peripheral tissues, all 4 viral genome configurations showed low AAV biodistribution, though delivery of viral genomes comprising a CB6 promoter TAU_ITR3 (SEQ ID NO: 1992; CB6-HFF2AL) and TAU_ITR11 (SEQ ID NO: 2000; CB6-LF2AH) exhibited a slight, statistically non-significant trend toward enhanced expression in liver and skeletal muscle. IV administration of each of the four viral genomes tested resulted in greater AAV biodistribution in CNS tissues as compared to peripheral tissues.

Samples of hippocampus, cortex, olfactory bulb, thalamus, brainstem, spinal cord, liver, spleen, skeletal muscle and serum were subjected to analysis by ePHF ELISA to determine IPN002 expression from each of the four cell-type specific IPN002 viral genomes tested. Control studies were performed to confirm the standard curve and determine that the matrix effect is not observed in this ELISA assay. IPN002 antibody expression was then normalized to the viral genome biodistribution (IPN002/VG). Data are shown in Table 103 below as ng/mg protein (or ng/mL for serum samples) and IPN002/vg (shortened to ab/vg).

TABLE 103 IPN002 expression from ssVOY101.IPN002 constructs (ng/mg protein or mL) TAU_ITR2 TAU_ITR9 TAU_ITR3 TAU_ITR11 Vehicle (CAG-HL) (CAG-LH) (CB6-HL) (CB6-LH) (PBS) ng/mg ab/vg ng/mg ab/vg ng/mg ab/vg ng/mg ab/vg ng/mg ab/vg Hippocampus 7.6 1.1 10.4 1.4 1.6 0.1 6.2 0.4 0.0 0.0 Cortex 8.6 0.5 11.6 0.8 3.7 0.2 10.0 0.3 0.0 0.0 Olfactory Bulb 5.0 0.6 13.6 2.1 1.1 0.1 6.3 0.5 0.0 0.0 Thalamus 8.2 0.4 14.4 0.9 4.1 0.1 9.4 0.2 0.0 0.0 Brainstem 13.9 0.7 26.2 1.4 9.6 0.4 16.3 0.4 0.0 0.0 Spinal Cord 23.8 2.1 14.6 1.5 7.4 0.5 11.2 0.4 0.0 0.0 Liver 9.9 3.5 14.7 11.0 3.0 0.8 0.9 0.2 0.1 0.0 Spleen 11.5 19.3 10.1 12.1 0.2 0.0 0.9 0.6 0.0 0.0 Muscle 36.7 119.3 21.9 44.2 1.8 3.5 2.0 1.9 0.0 0.0

IPN002 expression was evident in all CNS tissues tested an limited expression was seen in the peripheral tissues of mice treated with each of the four viral genomes. Comparison of IPN002 expression from viral genomes of the same configuration other than for the promoter (CAG-HF.F2AL vs. CB6-HF.F2AL) showed greater expression driven by the CAG promoter than the CB6 promoter. The trend for greater IPN002 expression when using the CAG promoter was also evident when assessed per viral genome (normalized to viral genome biodistribution; ab/vg).

In a direct comparison of viral genomes comprising ubiquitous promotors and either a T2A or F2A linker, eight viral genomes were tested (TAU_ITR1 (SEQ ID NO: 1990: CAG-HF.T2AL), TAU_ITR10 (SEQ ID NO: 1999: CAG-LT2AH), TAU_ITR4 (SEQ ID NO: 1993; CB6-HF.T2AL), and TAU_ITR87 (SEQ ID NO: 2137; CB6-LT2AH), TAU_ITR2 (SEQ ID NO: 1991; CAG-HF.F2AL), TAU_ITR9 (SEQ ID NO: 1998: CAG-LF2AH), TAU_ITR3 (SEQ ID NO: 1992; CB6-HF.F2AL), and TAU_ITR11 (SEQ ID NO: 2000: CB6-LF2AH)) by ePHF ELISA (Table 104) for IPN002 antibody expression (ng/mg). Table 105 shows IPN002 antibody expression normalized to viral genome biodistribution (IPN002/VG).

TABLE 104 IPN002 expression from ssVOY101.IPN002 constructs (ng/mg protein) CAG-HL CAG-LH CB6-HL T2A F2A T2A F2A T2A (TAU_ITR1) (TAU_ITR2) (TAU_ITR10) (TAU_ITR9) (TAU_ITR4) SEQ ID NO: 1990 1991 1999 1998 1993 Hippocampus 62.7 7.6 48.0 10.4 35.9 Cortex 106.1 8.6 62.3 11.6 54.8 Olfactory 72.6 5.0 44.2 13.6 35.3 Bulb Thalamus 59.0 8.2 46.7 14.4 40.1 Brainstem 138.5 13.9 69.6 26.2 111.9 Spinal Cord 124.3 23.8 150.3 14.6 78.7 Serum 131274 87446.7 1452.54 76889.3 26251.2 (ng/mL) CB6-HL CB6-LH F2A T2A F2A Vehicle (PBS) (TAU_ITR3) (TAU_ITR87) (TAU_ITR11) T2A F2A SEQ ID NO: 1992 2137 2000 — — Hippocampus 1.6 44.2 6.2 0.0 0.0 Cortex 3.7 22.3 10.0 0.0 0.0 Olfactory 1.1 27.5 6.3 0.0 0.0 Bulb Thalamus 4.1 16.0 9.4 0.0 0.0 Brainstem 9.6 60.5 16.3 0.0 0.0 Spinal Cord 7.4 34.0 11.2 0.0 0.0 Serum 7688.1 30185.2 1792.3.1 0.0 0.0 (ng/mL)

TABLE 105 Normalized IPN002 expression from ssVQY101.IPN002 constructs CAG-HL CAG-LH CB6-HL T2A F2A T2A F2A T2A (TAU_ITR1) (TAU_ITR2) (TAU_ITR10) (TAU_ITR9) (TAU_ITR4) SEQ ID NO: 1990 1991 1999 1998 1993 Hippocampus 9.7 1.1 6.6 1.4 3.8 Cortex 12.4 0.5 4.6 0.8 2.6 Olfactory 23.1 0.6 9.3 2.1 5.9 Bulb Thalamus 6.6 0.1 3.3 0.9 1.8 Brainstem 14.9 0.7 11.1 1.4 5.4 Spinal Cord 24.3 2.1 28.5 1.5 4.6 CB6-HL CB6-LH F2A T2A F2A Vehicle (PBS) (TAU_ITR3) (TAU_ITR87) (TAU_ITR11) T2A F2A SEQ ID NO: 1992 2137 2000 — — Hippocampus 0.1 2.9 0.4 0.0 0.0 Cortex 0.2 0.6 0.3 0.0 0.0 Olfactory 0.1 1.6 0.5 0.0 0.0 Bulb Thalamus 0.1 0.4 0.4 0.0 0.0 Brainstem 0.4 1.7 0.4 0.0 0.0 Spinal Cord 0.5 1.4 0.4 0.0 0.0

In CNS tissues of mice, use of the T2A linker, rather than the F2A, led to higher expression of IPN002 from viral genomes comprising cither a CAG or CB36 promoter and having an HFF2AL or LF2AH configuration, as determined by, ELISA. Analysis based on normalization to viral genome biodistribution demonstrated that IPN002 expression was increased when driven by the CAG, rather than the CB6 promoter, and that the heavy-linker-light configuration yielded higher antibody expression than the light-linker-heavy configuration. These findings were supported by measurement of IPN002 antibody levels in serum samples, by ePHF ELISA, which showed higher levels of IPN002 expression when driven by the CAG promoter than by the CB6 promoter. Delivery of viral genomes comprising a T2A linker, rather than an F2A linker, yielded greater serum levels of IPN002.

Anti-IgG immunohistochemistry of brain tissue collected from mice 28 days after treatment with an IV bolus injection of ssVOY101.IPN002 AAV particles comprising viral genomes encoding IPN002, driven by either CAG or CB6 promoters and one of two viral genome configurations (HF.F2AL or LF2AH), showed broad antibody expression across the mouse CNS, but stronger staining in tissue of mice treated with heavy chain-linker-light chain configuration, as compared to light-linker-heavy configuration. Vehicle-treated control animals exhibited low background levels of staining. Expression of IPN002 antibody was observed in a non-cell type specific manner (neurons and astrocytes showed staining) across multiple brain regions, as may be expected when using ubiquitous promoters.

Immunohistochemistry of brain tissue of mice, treated with an IV bolus injection of ssVOY101.IPN102 AAV particles comprising viral genomes encoding IPN002, driven by CAG or CB6 promoters 28 days prior, for IPN002 (IgG) and astrocytic (S100β) markers showed co-localization of IPN002 with S100β positive cells.

Comparison of IPN002 antibody expression in the brain tissue of mice treated with TAU_ITR2 (SEQ ID NO: 1991: CAG-HF.F2AL) and TAU_ITR9 (SEQ ID NO: 1998; CAG-LF2AH) by immunohistochemistry for IPN002 (IgG) and astrocytes (S100β) showed IPN002 expression in several brain regions of mice treated with TAU_ITR2 (SEQ ID NO: 1991; CAG-HF.F2AL), but very little expression of IPN002 in the brain tissue of mice treated with TAU_ITR9 (SEQ ID NO: 1998; CAG-LF2AH). Co-localization of IPN002 (IgG) and S100β was identified. Comparison of viral genomes differing only by linker sequence (e.g., CAG HFT2AL vs CAG-HFF2AL) showed similar staining patterns when assessed by immunohistochemistry.

Comparison of IPN002 antibody expression in the brain tissue of mice treated with TAU_ITR3 (SEQ ID NO: 1992; CB6-HF.F2AL) and TAU_ITR11 (SEQ ID NO: 2000; CB6-LF2AH) by immunohistochemistry for IPN002 (IgG) and astrocytes (S100β) showed IPN002 expression in several brain regions of mice treated with TAU_ITR3 (SEQ ID NO: 1992; CB6-HF.F2AL), but very little expression of IPN002 in the brain tissue of mice treated with TAU_ITR11 (SEQ ID NO: 2000: CB6-LF2AH). Co-localization of IPN002 (IgG) and S100β was identified. Comparison of viral genomes differing only by linker sequence (e.g., CAG HFT2AL vs CAG-HFF2AL) showed similar staining patterns when assessed by immunohistochemistry.

Comparison of IPN002 antibody expression in the brain tissue of mice treated with TAU_ITR2 (SEQ ID NO: 1991; CAG-HF.F2AL) or TAU_ITR3 (SEQ ID NO: 1992: CB6-HF.F2AL) and TAU_ITR1 (SEQ ID NO: 1990: CAG-HT2AL) or TAU_ITR4 (SEQ ID NO: 1993; CB6-HT2AL) by immunohistochemistry for IPN002 (IgG) and astrocytes (S100β) showed enhanced IPN002 expression when driven by the CAG promoter, as opposed to the CB6 promoter.

Co-localization studies based on immunofluorescent staining for IPN002 and NeuN in cortex, hippocampus and thalamus of mice treated with heavy-linker-light viral genomes showed IPN002 expression in neuronal cells (NeuN positive cells) driven by the CAG or CB6 promoters.

Immunohistochemical analysis demonstrated strong IPN002 antibody expression in the CNS of mice treated with viral genomes utilizing a ubiquitous CAG or CB6 promoter. Viral genomes with heavy-linker-light configurations showed increased IPN002 expression as compared to light-linker-heavy configurations.

Taken together, these data indicate that ubiquitous CAG or CB6 promoters may effectively drive IPN002 expression in CNS tissue of mice, with limited concomitant expression in peripheral tissues (e.g., liver, spleen and muscle). High levels of IPN002 were observed in serum samples of treated mice. Expression of IPN002 in CNS and serum, as measured by PHF ELISA was increased when viral genomes comprising the T2A (rather than F2A) linker were used for IPN002 expression.

Cell-Type Specific Promoters for IPN002 Expression

The effect of using cell-type specific promoters GFAP or synapsin for driving expression of IPN002 from two different viral genome configurations (HF.T2AL or LT2AH) was assessed based on measurement of brain distribution, cellular tropism and expression level.

Viral genomes TAU_ITR6 (SEQ ID NO: 1995; GFAP-HF.T2AL), TAU_ITR13 (SEQ ID NO: 2002: GFAP-LT2AH), TAU_ITR8 (SEQ ID NO: 1997: SYN-HF.T2AL), and TAU_ITR15 (SEQ ID NO: 2004; SYN-LT2AH), were packaged into VOY101 AAV particles and formulated in PBS and 0.001% F-68. Vehicle PBS with 0.001% F-68 was used as a control. An intravenous bolus at a dose of 1.4×10¹³ vg/kg was administered via tail vein to two-month old female C57Bl/6 mice (n=4 per group: 20 total mice). Twenty-eight days later, mice were sacrificed by intracardiac perfusion and tissue samples collected and processed for further analysis. The right half of the brain (including olfactory bulb) and lumbar spinal cord were post-fixed with 4% PFA for immunohistochemistry. The other half of the brain (dissected into hippocampus, cortex, thalamus, brainstem) and cervical and thoracic spinal cord tissues were processed for use in ELISA assays and vector genome quantification by droplet digital PCR normalized to diploid cell number (VG/DC) using the endogenous transferrin receptor gene (TFRC). Peripheral tissues from spleen, liver and skeletal muscle were also collected. Serum samples were collected at two days prior to dosing, and weekly after dosing on days 7, 14, 21 and 28 (terminal day). CSF samples were collected on the terminal day (D28). The study design is shown in Table 106 below.

TABLE 106 ssVOY101.IPN002 GFAP/SYN promoter study design SEQ End Construct TAU_ITR ID Dose Dose of Configuration ID NO: μL (vg/kg) (vg) Route N study GFAP-HF.T2AL TAU_ITR6 1995 100 1.4E13 2.8E11 IV 4 D 28 GFAP-LT2AH TAU_ITR13 2002 100 1.4E13 2.8E11 IV 4 D 28 SYN-HF.T2AL TAU_ITR8 1997 100 1.4E13 2.8E11 IV 4 D 28 SYN-LT2AH TAU_ITR15 2004 100 1.4E13 2.8E11 IV 4 D 28 PBS with 0.001% F-68 — — 100 — — IV 4 D 28

CNS, peripheral and serum samples were analyzed by ePHF ELISA. Brain, olfactory bulb and spinal cord tissues were assessed by immunohistochemistry (NeuN. S100b, Iba), immunofluorescence and/or hematoxylin and eosin staining (H&E). Vector genome quantification using droplet digital PCR (ddPCR) was carried out for samples collected from cortex, hippocampus, anterior olfactory bulb, brain stem, thoracic spinal cord, liver and skeletal muscle. Secondary readouts included daily cage side observations for 1 week after AAV particle administration and weekly body weight measurements. Vector genome quantifications (VG/DC) are shown in the Table 107 below.

TABLE 107 Vector genome quantification of ssVOY101.IPN002 constructs TAU_ITR6 TAU_ITR13 TAU_ITR8 TAU_ITR15 Vehicle (GFAP-HL) (GFAP-LH) (SYN-HL) (SYN-LH) (PBS) Hippocampus 8.7 21.2 13.4 10.1 0.0 Cortex 11.6 27.0 20.0 20.5 0.0 Olfactory Bulb 5.5 14.2 8.4 11.6 0.0 Thalamus 14.7 40.3 23.4 20.2 0.0 Brainstem 13.5 39.4 25.3 16.8 0.0 Spinal Cord 7.7 22.6 13.0 13.5 0.0 Liver 0.7 6.4 3.5 2.4 0.0 Skeletal Muscle 0.1 0.4 0.2 0.3 0.0 Spleen 0.3 0.7 0.2 2.0 0.0

Across the six CNS tissues analyzed, three (GFAP-HF.T2AL, SYN-HF.T2AL and SYN-LT2AH) of the four viral genome configurations resulted in similar AAV biodistribution. A slight increase in CNS biodistribution was seen with TAU_ITR13 (SEQ ID NO: 2002: GFAP-LT2AH), however this difference was not found to be statistically significant. In peripheral tissues, all 4 viral genome configurations showed low AAV biodistribution.

Samples of hippocampus, cortex, olfactory bulb, thalamus, brainstem, spinal cord, liver, spleen, skeletal muscle and serum were subjected to analysis by ePHF ELISA to determine IPN002 expression from each of the four cell-type specific IPN002 viral genomes tested. Control studies were performed to confirm the standard curve and determine that the matrix effect is not observed in this ELISA assay. IPN002 antibody expression was then normalized to the viral genome biodistribution (IPN002/VG). Data are shown in Table 108 below as ng/mg protein (or ng/mL for serum samples) and IPN002/vg (shortened to ab/vg). Data for one mouse were omitted since no vector genomes were detected.

TABLE 108 IPN002 expression from ssVOY101.IPN002 constructs (ng/mg protein or mL) TAU_ITR6 TAU_ITR13 TAU_ITR8 TAU_ITR15 Vehicle (GFAP-HL) (GFAP-LH) (SYN-HL) (SYN-LH) (PBS) ng/mg ab/vg ng/mg ab/vg ng/mg ab/vg ng/mg ab/vg ng/mg ab/vg Hippocampus 47.6 5.1 20.0 0.9 40.4 3.0 11.6 0.9 0.0 0.0 Cortex 66.5 5.5 32.8 1.3 64.9 3.3 21.0 1.1 0.0 0.0 Olfactory Bulb 118.3 21.5 63.4 4.7 104.0 9.2 26.9 2.7 0.0 0.0 Thalamus 32.2 2.1 26.6 0.9 69.3 3.0 20.3 1.0 0.0 0.0 Brainstem 53.3 4.0 42.0 1.1 119.5 3.5 28.6 1.9 0.0 0.0 Spinal Cord 29.3 3.8 24.4 1.0 123.8 7.8 27 7 2.3 0.0 0.0 Liver 8.7 12.7 18.0 3.9 0.7 0.1 0.2 0.1 0.0 0.0 Serum (ng/mL) 40202.8 — 86884.3 — 6652.4 — 5025.3 — 0.0 0.0 Spleen 9.8 83.3 5.2 8.7 0.7 3.6 0 0 0.0 0.0 Skeletal muscle 8.3 — 7.5 — 0.9 — 0.3 — 0.0 0.0

IPN002 expression was limited in the peripheral tissues in samples collected from mice treated with each of the four viral genomes, as compared to expression in CNS tissues. In all CNS tissues tested, the heavy-linker-light viral genome configuration (TAU_ITR6 and TAU_ITR8) yielded greater IPN002 expression than the light-linker-heavy viral genome configuration (TAU_ITR13 and TAU_ITR15). This result is consistent with the findings of the study comparing ubiquitous CAG and CB6 promoters.

Comparison of IPN002 antibody expression in the brain tissue of mice treated with TAU_ITR6 (SEQ ID NO: 1995; GFAP-HF.T2AL) and TAU_ITR13 (SEQ ID NO: 2002; GFAP-LT2AH) by immunohistochemistry for IPN002 (IgG) and astrocytes (S100β) showed IPN002 expression in several brain regions of mice treated with TAU_ITR6 (SEQ ID NO: 1995; GFAP-HF.T2AL), but very little expression of IPN002 in the brain tissue of mice treated with TAU_ITR13 (SEQ ID NO: 2002; GFAP-LT2AH). Co-localization of IPN002 (IgG) and S100β was identified.

Immunohistochemical staining for IPN002 (IgG) and S100β in brain tissue of mice treated with TAU_ITR8 (SEQ ID NO: 1997; SYN-HF.T2AL), and TAU_ITR15 (SEQ ID NO: 2004; SYN-LT2AH), showed IPN002 expression in several brain regions of mice treated with TAU_ITR8 (SEQ ID NO: 1997; SYN-HF.T2AL), with IPN002 predominantly expressed in cells with neuronal morphology in the hippocampus, cortex and thalamus. Limited IPN002 expression was evident in brain tissue of mice treated with TAU_ITR15 (SEQ ID NO: 2004; SYN-LT2AH). No co-localization of IPN002 and S100β in these samples was identified.

Immunofluorescence staining of samples collected from mice treated with each of the four vectors confirmed findings that IPN002 expression was readily detected in the tissue of mice treated with TAU_ITR6 (SEQ ID NO: 1995; GFAP-HF.T2AL) or TAU_ITR8 (SEQ ID NO: 1997; SYN-HF.T2AL), but not in tissue of mice treated with TAU_ITR13 (SEQ ID NO: 2002; GFAP-LT2AH) or TAU_ITR15 (SEQ ID NO: 2004; SYN-LT2AH), indicating the importance of a heavy-linker-light viral genome when matched with a cell-type specific promoter such as GFAP or synapsin.

Co-localization studies based on immunofluorescent staining for IPN002 and NeuN showed IPN002 expression in neuronal cells in the tissue of mice treated with heavy-linker-light viral genomes driven by the synapsin promoter. IPN002 expressed from heavy-linker-light viral genomes driven by the GFAP promoter was present in cells with astrocytic morphology.

Immunohistochemical analysis demonstrated strong and appropriate cell specificity of GFAP and synapsin promoters in the brain tissue of treated mice. Further, immunohistochemical results were consistent with those observed by ELISA assay.

Taken together, these data indicate that GFAP and synapsin promoters may effectively drive IPN002 expression in brain tissue of mice and support the previous finding that use of the vector genome configuration HF.T2AL can lead to approximately 2-fold greater IPN002 expression than configuration LT2AH.

Cell-Type Specific Promoters and 72A or F2A Linkers for IPN002 Expression

In a second study, the effect of using cell-type specific promoters GFAP or synapsin for driving expression of IPN002 from two different viral genome configurations (HF.F2AL or LF2AH) was assessed based on measurement of brain distribution, cellular tropism and antibody expression level. Data from this study further enabled comparison of the effects of T2A and F2A cleavage sites on IPN002 antibody expression, distribution and tropism.

Viral genomes TAU_ITR5 (SEQ ID NO: 1994; GFAP-HF.F2AL), TAU_ITR12 (SEQ ID NO: 2001; GFAP-LF2AH), TAU_ITR7 (SEQ ID NO: 1996; SYN-HF.F2AL), and TAU_ITR14 (SEQ ID NO: 2003; SYN-LF2AH), were packaged, single stranded, into VOY101 AAV particles and formulated in PBS and 0.001% F-68. Vehicle PBS with 0.001% F-68 was used as a control. An intravenous bolus at a dose of 1.4×10¹³ vg/kg was administered via tail vein to two-month old female C57Bl/6 mice (n=4 per group; 20 total mice). Twenty-eight days later, mice were sacrificed by intracardiac perfusion and tissue samples collected and processed for further analysis. The right half of the brain (including olfactory bulb) and lumbar spinal cord were post-fixed with 4% PFA for immunohistochemistry. The other half of the brain (dissected into hippocampus, cortex, thalamus, brainstem) and cervical and thoracic spinal cord tissues were processed for use in ELISA assays and vector genome quantification by droplet digital PCR normalized to diploid cell number (VG/DC) using the endogenous transferrin receptor gene (TFRC). Peripheral tissues from spleen, liver and skeletal muscle were also collected. Serum samples were collected at two days prior to dosing, and weekly after dosing on days 7, 14, 21 and 28 (terminal day). CSF samples were collected on the terminal day (D28). The study design is shown in Table 109 below.

TABLE 109 ssVOY101.1PN002 GFAP/SYN promoter and linker study design SEQ End Construct TAU_ITR ID Dose Dose of Configuration ID NO: μL (vg/kg) (vg) Route N study GFAP-HF.F2AL TAU_ITR5 1994 100 1.4E13 2.8E11 IV 4 D 28 GFAP-LF2AH TAU_ITR12 2001 100 1.4E13 2.8E11 IV 4 D 28 SYN-HF.F2AL TAU_ITR7 1996 100 1.4E13 2.8E11 IV 4 D 28 SYN-LF2AH TAU_ITR14 2003 100 1.4E13 2.8E11 IV 4 D 28 PBS with 0.001% F-68 — — 100 — — IV 4 D 28

CNS, peripheral and serum samples were analyzed by ePHF ELISA. Brain, olfactory bulb and spinal cord tissues were assessed by immunohistochemistry (NeuN, S100β, IgG), immunofluorescence and/or hematoxylin and eosin staining (H&E). Vector genome quantification using droplet digital PCR (ddPCR) was carried out for samples collected from cortex, hippocampus, anterior olfactory bulb, brain stem, thoracic spinal cord, liver and skeletal muscle. Secondary readouts included daily cage side observations for 1 week after AAV particle administration and weekly body weight measurements. Vector genome quantifications (VG/DC) are shown in the Table 110 below.

TABLE 110 Vector genome quantification of ssVOY101.IPN002 constructs TAU_ITR5 TAU_ITR12 TAU_ITR7 TAU_ITR14 Vehicle (GFAP-HL) (GFAP-LH) (SYN-HL) (SYN-LH) (PBS) Hippocampus 8.4 11.3 14.7 17.0 0.0 Cortex 17.7 22.8 29.2 32.1 0.0 Olfactory Bulb 5.8 9.8 11.8 13.7 0.0 Thalamus 20.1 25.9 31.8 28.5 0.0 Brainstem 21.4 22.1 32.1 36.8 0.0 Spinal Cord 12.0 15.5 18.9 19.1 0.0 Liver 1.8 1.4 1.1 4.9 0.0 Skeletal Muscle 0.6 0.9 0.8 1.0 0.0 Spleen 0.3 0.4 0.6 1.2 0.0

Across the six CNS tissues analyzed, treatment with each of the four viral genome configurations resulted in similar AAV biodistribution, with no statistically significant difference between treatment groups. In peripheral tissues, all 4 viral genome configurations showed low AAV biodistribution, though delivery of TAU_ITR14 (SEQ ID NO: 2003; SYN-LF2AH) exhibited a slight, statistically non-significant trend toward enhanced expression in liver and skeletal muscle. IV administration of each of the four viral genomes tested resulted in greater AAV biodistribution in CNS tissues as compared to peripheral tissues.

Samples of hippocampus, cortex, olfactory bulb, thalamus, brainstem, spinal cord, liver, spleen, skeletal muscle and serum were subjected to analysis by ePHF ELISA to determine IPN002 expression from each of the four cell-type specific IPN002 viral genomes tested. Control studies were performed to confirm the standard curve and determine that the matrix effect is not observed in this ELISA assay. IPN002 antibody expression was then normalized to the viral genome biodistribution (IPN002/VG). Data are shown in Table 111 below as ng/mg protein (or ng/mL for serum samples) and IPN002/vg (shortened to ab/vg).

TABLE 111 IPN002 expression from ssVOY101.IPN002 constructs (ng/mg protein or inL) TAU_ITR5 TAU_ITR12 TAU_ITR7 TAU_ITR14 Vehicle (GFAP-HL) (GFAP-LH) (SYN-HL) (SYN-LH) (PBS) ng/mg ab/vg ng/mg ab/vg ng/mg ab/vg ng/mg ab/vg ng/mg ab/vg Hippocampus 1.6 0.2 9.8 0.8 20.5 1.5 17.5 1.1 0.0 0.0 Cortex 1.8 0.1 8.0 0.4 5.7 0.2 7.4 0.2 0.0 0.0 Olfactory Bulb 1.8 0.2 10.4 0.8 14.9 1.1 19.6 1.5 0.0 0.0 Thalamus 1.4 0.0 9.5 0.3 10.7 0.3 19.9 0.7 0.0 0.0 Brainstem 2.7 0.1 11.3 0.5 16.7 0.6 20.1 0.6 0.0 0.0 Spinal Cord 4.2 0.3 7.0 0.4 20.7 1.2 12.6 0.7 0.0 0.0 Liver 1.1 1.0 2.0 2.2 0.0 0.0 0.2 0.0 0.0 0.0 Serum (ng/mL) 4563.8 — 28318 — 994.2 — 2445.4 — 0.0 0.0 Spleen 1.9 2.4 6.0 5.9 0.0 0.0 0.0 0.0 0.0 0.0 Skeletal muscle 3.0 10.6  6.5 15.6  0.2 0.3 0.2 0.3 0.0 0.0

IPN002 expression was evident in all CNS tissues tested and limited expression was seen in the peripheral tissues of mice treated with each of the four viral genomes. In this study, there was no clear pattern for enhanced antibody expression with one particular viral genome configuration as compared to the others, as was seen in the prior experiment using a T2A cleavage site.

In a direct comparison of viral genomes comprising cell-specific promotors and either a T2A or F2A linker, eight viral genomes were tested (TAU_ITR6 (SEQ ID NO: 1995; GFAP-HF.T2AL), TAU_ITR13 (SEQ ID NO: 2002; GFAP-LT2AH) TAU_ITR8 (SEQ ID NO: 1997; SYN-HF.T2AL), and TAU_ITR1 (SEQ ID NO: 2004 SYN-LT2AH), TAU_ITR5 (SEQ ID NO: 1994; GFAP-HF.F2AL) TAU_ITR12 (SEQ ID NO: 2001; GFAP-LF2AH) TAU_ITR7 (SEQ ID NO: 1996m SYN-HF.F2AL), and TAU_ITR14 (SEQ ID NO: 2003. SYN-LF2AH)) by IgG (Table 112) and ePHF ELISA (Table 113) for IPN002 antibody expression (ng/mg). Table 114 shows IPN002 antibody expression normalized to viral genome biodistribution (IPN002/VG)

TABLE 112 IPN002 expression from ssVOY101.IPN002 constructs (ng/mg protein) GFAP-HL GFAP-LH SYN-HL T2A F2A T2A F2A T2A (TAU_ITR6) (TAU_ITR5) (TAU_ITR13) (TAU_ITR12) (TAU_ITR8) SEQ ID NO: 1995 1994 2002 2001 1997 Hippocampus 90.5 16.0 128.5 22.4 98.2 Cortex 112.0 15.8 67.5 24.8 71.5 Olfactory 150.7 30.1 123.9 58.0 161.1 Bulb SYN-HL SYN-LH Vehicle F2A T2A F2A (PBS) (TAU_ITR7) (TAU_ITR15) (TAU_ITR14) T2A F2A SEQ ID NO: 1996 2004 2003 — — Hippocampus 30.3 66.5 28.1 0.0 0.0 Cortex 17.6 46.5 26.3 10.9 4.3 Olfactory 48.5 17.2 51.3 0.0 7.9 Bulb

TABLE 113 IPN002 expression from ssVOY101.IPN002 constructs (ng/mg protein) GFAP-HL GFAP-LH SYN-HL T2A F2A T2A F2A T2A (TAU_ITR6) (TAU_ITR5) (TAU_ITR13) (TAU_ITR12) (TAU_ITR8) SEQ ID NO: 1995 1994 2002 2001 1997 Hippocampus 47.6 1.6 20.0 9.8 30.3 Conex 66.5 1.8 32.9 8.0 48.7 Olfactory 118.3 1.8 63.4 10.4 78.0 Bulb Thalamus 32.2 1.4 26.6 9.5 60.0 Brainstem 53.3 2.7 42.0 11.3 89.6 Spinal Cord 29.3 4.2 24.2 1.5 92.9 Serum 39769.8 4563.8 94211.6 28318 5861.8 (ng/mL) SYN-HL SYN-LH Vehicle F2A T2A F2A (PBS) (TAU_ITR7) (TAU_ITR15) (TAU_ITR14) T2A F2A SEQ ID NO: 1996 2004 2003 — — Hippocampus 20.5 11.6 17.5 0.0 0.0 Conex 5.7 21.0 7.4 0.0 0.0 Olfactory 14.9 26.9 19.6 0.0 0.0 Bulb Thalamus 10.7 20.3 19.9 0.0 0.0 Brainstem 16.7 28.6 20.1 0.0 0.0 Spinal Cord 20.7 27.7 12.6 0.0 0.0 Serum 994.2 456.3.3 2445.4 0.0 0.0 (ng/mL)

TABLE 114 Normalized IPN002 expression from ssVOY101.IPN002 constructs GFAP-HL GFAP-LH SYN-HL T2A F2A T2A F2A T2A (TAU_ITR6) (TAU_ITR5) (TAU_ITR13) (TAU_ITR12) (TAU_ITR8) SEQ ID NO: 1995 1994 2002 2001 1997 Hippocampus 5.1 0.2 0.9 0.8 3.0 Cortex 5.5 0.1 1.3 0.4 3.7 Olfactory 21.5 0.2 4.7 0.8 9.2 Bulb Thalamus 2.1 0.0 0.9 0.3 2.4 Brainstem 4.0 0.1 1.1 0.5 3.5 Spinal Cord 3.8 0.3 1.0 0.4 5.9 SYN-HL SYN-LH Vehicle F2A T2A F2A (PBS) (TAU_ITR7) (TAU_ITR15) (TAU_ITR14) T2A F2A SEQ ID NO: 1996 2004 2003 — — Hippocampus 1.5 0.9 1.1 0.0 0.0 Cortex 0.2 1.1 0.2 0.0 0.0 Olfactory 1.1 2.7 1.5 0.0 0.0 Bulb Thalamus 0.3 1.0 0.7 0.0 0.0 Brainstem 0.6 1.9 0.6 0.0 0.0 Spinal Cord 1.2 1.0 0.7 0.0 0.0

In general, use of the T2A linker, rather than the F2A, led to higher expression of IPN002 from viral genomes comprising either a GFAP or synapsin promoter and having an HFF2AL or LF2AH configuration, as determined by ELISA. Serum levels of IPN002 antibody were greater with use of the GFAP promoter rather than the synapsin promoter and were greater when the T2A linker, rather than F2A linker, was used.

Comparison of IPN002 antibody expression in the brain tissue of mice treated with TAU_ITR5 (SEQ ID NO: 1994; GFAP-HF.F2AL) and TAU_ITR12 (SEQ ID NO: 2001; GFAP-LF2AH) by immunohistochemistry for IPN002 (IgG) and astrocytes (S100β) showed IPN002 expression in several brain regions of mice treated with TAU_ITR5 (SEQ ID NO: 1994; GFAP-HF.F2AL), but very little expression of IPN002 in the brain tissue of mice treated with TAU_ITR12 (SEQ ID NO: 2001; GFAP-LF2AH). Co-localization of IPN002 (IgG) and S100β was identified. These findings are very similar to those seen with the use of a T2A linker, above.

Immunohistochemical staining for IPN002 (IgG) and S100β in brain tissue of mice treated with TAU_ITR7 (SEQ ID NO: 1996; SYN-HF.F2AL), and TAU_ITR14 (SEQ ID NO: 2003; SYN-LF2AH), showed IPN002 expression in several brain regions of mice treated with TAU_ITR7 (SEQ ID NO: 1996; SYN-HF.F2AL), with IPN002 predominantly expressed in cells with neuronal morphology in the hippocampus, cortex and thalamus. Limited IPN002 expression was evident in brain tissue of mice treated with TAU_ITR14 (SEQ ID NO: 2003; SYN-LF2AH). No co-localization of IPN002 and S100β in these samples was identified. These findings are very similar to those seen with the use of a T2A linker, above.

Co-localization studies based on immunofluorescent staining for IPN002 and NeuN in cortex, hippocampus (CA subfields) and thalamus of mice treated with heavy-linker-light viral genomes showed IPN002 expression in neuronal cells driven by the synapsin promoter. IPN002 expressed from heavy-linker-light viral genomes driven by the GFAP promoter was present in cells with astrocytic morphology.

Immunohistochemical analysis demonstrated strong and appropriate cell specificity of GFAP and synapsin promoters in the brain tissue of treated mice. Viral genomes with heavy-linker-light configurations showed a trend toward increased IPN002 expression as compared to light-linker-heavy configurations.

Taken together, these data indicate that GFAP and synapsin promoters may effectively drive IPN002 expression in CNS tissue of mice, with limited concomitant expression in peripheral tissues (e.g., liver, spleen and muscle). Cell-type specific promoters (GFAP or synapsin) resulted in IPN002 expression levels comparable to those seen when expression was driven by ubiquitous promoters. High levels of IPN002 were observed in serum samples, particularly in serum of mice treated with ssVOY101.IPN002 using the GFAP promoter, as opposed to synapsin promoter. Expression of IPN002 in CNS and serum, as measured by PHF ELISA was increased when viral genomes comprising the T2A (rather than F2A) linker were used for IPN002 expression.

Testing of IPN002 Viral Genomes in Primary Neurons

Primary neuronal cultures were used for testing cell specificity, transduction efficiency and expression of IPN002 using the viral genomes outlined above, encapsulated in Voy101. For preparation of primary cultures, brain tissue was removed from CD1 mice at embryonic day 17 (E17) and meninges removed. The hippocampi and cortices were dissected out and digested with papain. Cells were counted and plated (17,500 cells/well) accordingly.

On the 4^(th) day in vitro (DIV4) cells were transduced with AAV particles (3E6, 1E6, 3.33E5, 1.11E5, 3.7E4 VG/cell) comprising the IPN002 encoding viral genomes or Voy101-GFP as a positive control. Untransduced neurons served as the negative control.

Constructs shown in the table below (Table 115), with IPN002 expression driven by ubiquitous or cell-type specific promoters were tested.

TABLE 115 IPN002 Constructs for in vitro testing in primary cultures SEQ Construct ID ID NO: Configuration TAU_ITR1 1990 CAG-IPN002-HFT2AL TAU_ITR10 1999 CAG-IPN002-LT2AH TAU_ITR2 1991 CAG-IPN002-HFF2AL TAU_ITR9 1998 CAG-IPN002-LF2AH TAU_ITR4 1993 CBA-IPN002-HFT2AL TAU_ITR87 2137 CBA-IPN002-LT2AH TAU_ITR11 2000 CBA-IPN002-LF2AH TAU_ITR3 1992 CBA-IPN002-HFF2AL TAU_ITR5 1994 GFAP-IPN002-HFF2AL TAU_ITR12 2001 GFAP-IPN002-LF2AH TAU_ITR6 1995 GFAP-IPN002-HFT2AL TAU_ITR13 2002 GFAP-IPN002-LT2AH TAU_ITR7 1996 SYN-IPN002-HFF2AL TAU_ITR14 2003 SYN-IPN002-LF2AH TAU_ITR8 1997 SYN-IPN002-HFT2AL TAU_ITR15 2004 SYN-IPN002-LT2AH

Cultures were confirmed to be approximately 60-70% neuronal as measured by NeuN staining, with 5-10% of cells staining positive for GFAP (astrocytes).

On DIV7, the supernatant was collected for analysis by mouse IgG ELISA and the cells fixed with (4% PFA and 4% sucrose in PBS for 15 min, followed by 3 PBS washes) for immunocytochemical experiments. Cells were stained by first blocking with 3% BSA and 0.05% saponin in PBS for 1 hour at room temperature. Primary antibodies for IgG, GFAP, and NeuN were incubated overnight at 4 C in blocking buffer then washed with four PBS washes. Secondary antibodies (1:1000 in blocking buffer) were incubated for 1 hour at room temperature then followed by four washes in PBS. Hoecsht was applied at 1:1000 in PBS at room temperature for 15 min to stain nuclei, then washed four times with PBS. Imaging was done on a BioTek Cytation 5.

As expected, cell-type specific promoters drove expression of IPN002 in the appropriate cell type, meaning that the synapsin promoter drove expression in neuronal cells while the GFAP promoter drove expression in astrocytes. These results are consistent with those of the in vivo studies described above.

The supernatant collected on DIV7 (3 days after transduction) was used with IgG1 mouse uncoated ELISA kit (ThermoFisher) for quantification of antibody/mL (ms IgG ng/mL). Of the viral genomes tested wherein a CAG promoter drove expression of IPN002, use of configuration CAG-IPN002-HFT2AL (TAU_ITR1; SEQ ID NO: 1990) resulted in the greatest expression. Similarly, testing of viral genomes wherein a CBA promoter drove expression of IPN002, use of configuration CBA-IPN002-HFT2AL (TAU_ITR4; SEQ ID NO: 1993) resulted in the greatest expression. These ELISA results were consistent with quantification of the immunocytochemistry for number of cells expressing IPN002/total number of cells. Direct comparison of configurations HFT2AL and LT2AH driven by CAG and CBA promoters, by ELISA and quantification of immunocytochemistry demonstrated the CAG promoter to drive greater expression of IPN002 in cells in primary culture and supported the findings that the HFT2AL configuration resulted in greater expression. Analysis of viral genome constructs wherein IPN002 expression is driven by a synapsin promoter by ELISA and quantification of immunocytochemistry again indicated enhanced expression from the HFT2AL configuration, as compared to LT2AH, HFF2AL and LF2AH configurations.

Studies in primary neuronal cultures supported the findings wherein CAG promoters, heavy-linker-light configurations and T2A linkers each contributed to more robust expression of IPN002 as compared to their correlate, i.e., CB6 promoters, light-linker-heavy configurations and F2A linkers, respectively.

Testing of PT3 Viral Genomes in Primary Culture

Viral genomes encoding anti-tau antibody PT3 with configuration HFT2AL and one of CAG, CBA, GFAP or synapsin promoters were tested in primary neuronal cultures for testing cell specificity, transduction efficiency and expression of PT3. The viral genome constructs shown in Table 116 below were encapsulated in AAV Voy101 and used to transduce primary neuronal cultures as described above.

TABLE 116 PT3 Constructs for in vitro testing in primary cultures SEQ Construct ID ID NO: Configuration TAU_ITR111 2161 CBA-PT3-HFT2AL TAU_ITR112 2162 CAG-PT3-HFT2AL TAU_ITR113 2163 GFAP-PT3-HFT2AL TAU_ITR114 2164 SYN-PT3-HFT2AL

As expected, cell-type specific promoters drove expression of PT3 in the appropriate cell type, meaning that the synapsin promoter drove expression in neuronal cells while the GFAP promoter drove expression in astrocytes.

Studies of viral genomes expressing PT3 demonstrated that IV dosing using a blood brain barrier penetrant capsid (e.g., VOY101) resulted in widespread vector genome biodistribution and expression of vectorized anti-tau antibody in mouse CNS, using each of the constructs tested. The incorporation of cell-type specific promoters targeted the antibody expression to a cellular subgroup. Use of a synapsin promoter was shown to drive PT3 expression in neuronal cells, while use of a GFAP promoter was shown to drive PT3 expression in astrocytes.

Antibody expression levels were shown to be influenced by the promoter choice and by the configuration of the viral genome. Heavy-linker-light configurations yielded greater PT3 antibody expression than light-heavy-linker configurations. Overall, these studies have shown that IV dosing of ssAAVVOY101.PT3 can effectively deliver vectorized antibody to the CNS of mice for both ubiquitous and cell-type specific antibody expression.

Viral Genomes for PHF1 Antibody Expression

Five viral genome variants were prepared to assess ITR to ITR and payload configuration effects on PHF1 antibody expression. Promoters, introns and heavy and light chain 5′ to 3′ order were assessed. Constructs tested included TAU_ITR86 (PHF-1 LF2AH), TAU_ITR85 (PHF-1 HF.F2AL), and TAU_ITR70 (PHF-1 LF2AH).

ExpiCHO cells were transfected with each of the PHF1 antibody expressing viral genome constructs to generate an antibody-rich supernatant. Samples of supernatant were prepared for analysis by Western blot, as described in Example 6 above. The resultant Western blots were reviewed for the presence of heavy (50 kD) and light chain (25 kD) species. Two of the three constructs yielded bands representing both heavy and light chain species. TAU_ITR85 gave no evidence of antibody expression, lacking bands at both 50 kD and 25 kD. TAU_ITR70 showed the greatest antibody expression, followed by TAU_ITR86, based on Western blot analysis.

Direct comparison of TAU_ITR70 and TAU_ITR86, comprising different intronic regions, indicated greater antibody expression with the use of human beta-globin intronic segments (TAU_ITR70) as compared to an SV40 intron (TAU_ITR86).

Two ELISA assays (PHF-1 IgG1 and anti-eTau) were also performed to determine antibody production from each of the three constructs. Results are shown in Table 17 below.

TABLE 117 ELISA for analysis of antibody production PHF-1 IgG1 Elisa: anti-eTau Elisa: Construct Name ng/ml ng/ml TAU_ITR86 15273.0 1526.5 TAU_ITR85 191.0 18.8 TAU_ITR70 25678.0 4285.0

Example 9. rAAV Production of Anti-Tau Antibodies Using HEK293T Cells

HEK293 cells were transfected with three vectors simultaneously: anti-tau antibody encoding viral genomes; vectors expressing rep and cap genes; and a helper vector to generate rAAV9 products. Vector production was the greatest (highest AAV titer vg/mL) when using MC1LF2AH (TAU_ITR79) and MC1HF.F2AL (TAU_ITR72) viral genomes. These two formats were then utilized to generate rAAV9 particles encoding anti-tau antibodies PHF1 and IPN002.

TABLE 118 Vector production in HEK293T cells (vg/mL) 1st 2nd Average AAV9.LIRESH 2.23E+10 3.00E+10 2.62E+10 AAV9.LF2AH 9.12E+10 2.69E+11 1.80E+11 AAV9.HF.F2AL 2.32E+10 1.24E+11 7.35E+10 AAV9.LF.F2AH 2.00E+10 1.15E+10 1.57E+10 AAV9.HF.P2AL 1.70E+10 2.63E+10 2.16E+10

Example 10. Construction of Viral Genomes for Expression of Antibody Fragments

Full-length antibodies have certain disadvantages in terms of incorporation into AAV viral genomes and particles, immunogenicity and blood brain barrier penetration, that can be overcome by encoding an antibody fragment instead of the full-length antibody. Antibody fragments (e.g., F(ab′)2, Fab and scFv) can be advantageous in several ways. While retaining their antigen-binding capacity, the smaller size of antibody fragments may allow for better tissue penetration and/or have increased solubility. Use of antibody fragments may also provide the opportunity to engage epitopes which may be hidden. As compared to fill-length antibodies, antibody fragments may have reduced immunogenicity and effector effects. Further, antibody fragments are typically straightforward to modify or engineer to one with skill in the art and may be more amenable to incorporation in AAV viral genomes and particles.

Antibody fragments were designed for incorporation into viral genomes and AAV particles. F(ab′)2, Fab and scFv fragments were designed. Fragments were sequence confirmed and tested in vitro for expression patterns. Western blotting was used for semi-quantitation, followed by ePHF ELISA and wild-type tau441 ELISA for further characterization. Based on these results, lead fragment constructs were selected, incorporated into viral genome constructs and packaged into AAV particles, then tested in vivo.

Viral Genomes for the Expression of PHF1 Fragments

Four constructs were generated for the expression of PHF-1 single chain variable fragments (scFv). Two viral genome configurations (light-linker-heavy and heavy-linker-light) and human growth hormone-2 (Signal1; SEQ ID NO: 2106) and PHF1 antibody heavy chain (Ab2; SEQ ID NO: 1741) signal sequences were tested for effects on the expression of PHF1 scFv and evaluated by western blot analysis as described in Example 6. These viral genomes encoded a His tag (TAG4; SEQ ID NO: 2121) which was used for labeling with anti-his HRP (1:5000 dilution) in Western blot experiments.

Each of the 4 constructs (TAU_ITR42 (LG4S3H-hGH2sig), TAU_ITR44 (LG4S3H-VLsig), TAU_ITR38 (HG4S3L-hGH2sig) and TAU_ITR40 (HG4S3L-VHsig) was transfected into Expi293 and ExpiCHO cells. Supernatants were collected and analyzed by Western blot. Four replicates were run for each construct. TAU_ITR42 and TAU_ITR40 each had one sample that showed no antibody expression based on Western blot analysis, while each of the other samples yielded a single prominent band indicating scFv expression. TAU_ITR38 and TAU_ITR40 (HG4S3L configuration) showed slightly elevated scFv expression, based on Western blot results.

Supernatants from transfected ExpiCHO and Expi293 cells were also tested for binding affinity to PHF tau, using the ePHF tau ELISA as described in Example 4. An anti-His HRP (1:5000) was used for detection. Untransfected ExpiCHO and Expi293 supernatants were used as control. OD450 data are shown below, in Table 119.

TABLE 119 PHF Tau ELISA: OD450 data Expi293 ExpiCHO dilution TAU_ITR42 TAU_ITR44 TAU_ITR38 TAU_ITR40 TAU_ITR42 1 1.4 1.5 2.9 3.0 1.3 4 0.5 0.6 2.7 2.7 0.7 16 0.3 0.3 2.1 2.1 0.4 64 0.2 0.2 1.6 1.5 0.2 256 0.1 0.1 0.8 0.7 0.1 1024 0.1 0.1 0.4 0.3 0.1 4096 0.1 0.0 0.1 0.1 0.1 16384 0.1 0.0 0.1 0.1 0.0 65536 0.0 0.0 0.0 0.0 0.0 262144 0.0 0.0 0.0 0.0 0.0 1048576 0.0 0.0 0.0 0.0 0.0 4194304 0.1 0.0 0.0 0.0 0.0 Controls ExpiCHO Expi293 ExpiCHO dilution TAU_ITR44 TAU_ITR38 TAU_ITR40 CTL CTL 1 1.4 3.1 3.0 0.0 0.1 4 0.7 2.9 2.8 0.0 0.0 16 0.4 2.6 2.5 0.0 0.0 64 0.3 2.1 2.0 0.0 0.0 256 0.1 1.4 1.3 0.0 0.0 1024 0.1 0.6 0.6 0.0 0.0 4096 0.1 0.2 0.3 0.0 0.0 16384 0.0 0.1 0.1 0.0 0.0 65536 0.0 0.1 0.1 262144 0.0 0.0 0.0 1048576 0.0 0.0 0.0 4194304 0.0 0.0 0.0

PHF1 scFvs generated from TAU_ITR38 and TAU_ITR40 viral genome constructs (both heavy-linker-light configuration) showed greater affinity for ePHF tau than scFvs generated from TAU_ITR42 and TAU_ITR44 viral genome constructs (both light-linker-heavy configuration), based on ePHF tau ELISA assay.

Viral Genomes for the Expression of IPN002 Fragments

Eighteen viral genomes were designed for the expression of anti-tau antibody IPN002 Fab, F(ab′)2, extended Fab, or scFv fragments, with components as outlined in Table 120 below. One of two promoters, CAG or CBA, was selected. Three configurations were tested (HF.T2AL, LT2AH, scFv), using each of the two promoters. For F(ab′)2 constructs one of two hinge components was also introduced. ScFv constructs alternated heavy chain or light chain first when read 5′ to 3′ and relied upon G4S linkers (“G4S” disclosed as SEQ ID NO: 4535) of variable lengths.

TABLE 120 Viral genomes for IPN002 fragment expression Intron/exon SEQ Promoter region Configuration Description Construct ID ID NO: CBA hGbin HF.T2AL F(ab′)2_hIgG3_2hinge TAU_ITR121 2171 F(ab′)2_hIgG3_3hinge TAU_ITR122 2172 Fab TAU_ITR123 2173 Fab_ext TAU_ITR124 2174 CAG — HF.T2AL F(ab′)2_hIgG3_2hinge TAU_ITR125 2175 F(ab′)2_hIgG3_3hinge TAU_ITR126 2176 Fab TAU_ITR127 2177 Fab_ext TAU_ITR128 2178 CBA hGbin LT2AH Fab_ext TAU_ITR129 2179 CAG — LT2AH Fab_ext TAU_ITR130 2180 CBA hGbin scFv-HA H(G4S)3L TAU_ITR133 2183 H(G4S)L TAU_ITR131 2181 L(G4S)3H TAU_ITR146 2196 L(G4S)H TAU_ITR144 2194 CAG — scFv-HA H(G4S)3L TAU_ITR139 2189 H(G4S)L TAU_ITR137 2187 L(G4S)3H TAU_ITR152 2202 L(G4S)H TAU_ITR150 2200

Anti-HA western blot of IPN002 scFv-HA viral genome constructs demonstrated bands at approximately 30 kd for each of the 8 constructs tested. Quantification data from anti-HA western blot and wtTau ELISA data are shown in the Table 121 below.

TABLE 121 IPN002 scFv-HA screening results SEQ Anti-HA wtTau Intron/exon Config- Construct ID WS ELISA Promoter region uration Description ID NO: μg/mL EC₅₀ CBA hGbin scFv-HA H(G4S)3L TAU_ITR133 2183 7.0 74.5 H(G4S)L TAU_ITR131 2181 2.3 423.3 L(G4S)3H TAU_ITR146 2196 41.9 37.9 L(G4S)H TAU_ITR144 2194 2.2 93.1 CAG scFv-HA H(G4S)3L TAU_ITR139 2189 10.5 29.5 H(G4S)L TAU_ITR137 2187 3.4 56.8 L(G4S)3H TAU_ITR152 2202 8.4 34.7 L(G4S)H TAU_ITR150 2200 4.8 232

IPN002 F(ab′)2, Fab and Fab_ext constructs were also assessed by western blot and tau ELISA assays. Western blot analysis of the 16 constructs outlined above showed a 30 kD band for all but two constructs. Viral genome contracts TAU_ITR121 (SEQ ID NO: 2171) and TAU_ITR125 (SEQ ID NO: 2175) showed no expression due to a mutation in the antibody encoding sequences. The remaining IPN002 F(ab′)2, Fab and Fab_ext viral genome constructs were assessed by tau ELISA and the results are shown in Tables 122 and 123 below.

TABLE 122 IPN002 HF.T2AL-Fab screening results SEQ wtTau PHF Tau Intron/exon Config- Construct ID ELISA ELISA Promoter region uration Description ID NO: EC₅₀ EC₅₀ CBA hGbin HF.T2AL Fab TAU_ITR123 2173 0.5 0.1 Fab_ext TAU_ITR124 2174 0.5 0.2 CAG HF.T2AL Fab TAU_ITR127 2177 0.5 0.1 Fab_ext TAU_ITR128 2178 0.6 0.1 Cells — — — — — 0.2 0.0 IPN002 — — — — — 0.3 0.0

TABLE 123 IPN002 LT2AFl-Fab screening results SEQ wtTau PHF Tau Intron/exon Config- Construct ID ELISA ELISA Promoter region uration Description ID NO; EC₅₀ EC₅₀ CBA hGbin LT2AH Fab_ext TAU_ITR129 2179 0.3 0.1 CAG — LT2AH Fab_ext TAU_ITR130 2180 0.3 0.1 Cells — — — — — 65.1 11.2 IPN002 — — — — — 0.2 0.0

These preliminary data indicate that viral genomes designed for expression of IPN002 Fab fragments, generate IPN002 Fabs that have affinity to and bind tau.

IPN002 F(ab)2 constructs were assessed in vitro by western blotting and ELISA. Under non-reduced conditions, each of the four IPN002 F(ab′)2 constructs outlined above, showed bands at approximately 150 kd based on western blot of 293 cell supernatant. In reduced conditions, all four constructs tested demonstrated a band between 25-30 kD. IPN002 F(ab′)2 constructs driven by CBA promoter were then tested by PHF-tau and wild-type tau ELISA, with data shown in the Table 124 below.

TABLE 124 IPN002 CBA-F(ab′)2 screening results SEQ wtTau PHF Tau Intron/exon Construct ID ELISA ELISA Promoter region Config. Description ID NO: EC₅₀ EC₅₀ CBA hGbin HF.T2AL F(ab′)2_hIgG3_2hinge TAU_ITR121 2171 109.1 48.9 F(ab′)2_hIgG3_3hinge TAU_ITR122 2172 116.7 64.3

IPN002 Fab constructs were assessed in vitro by western blotting and ELISA. Under non-reduced conditions, all of the IPN002 Fab constructs tested showed bands at approximately 23 kd based on western blot of 293 cell supernatant. In reduced conditions, all constructs tested demonstrated a band between 25-30 kD. IPN002 Fab constructs were then tested by PHF-tau and wild-type tau ELISA, with data shown in the Table 125 below.

TABLE 125 IPN002 Fab screening results SEQ wtTau PHF Tau Intron/exon Config- Construct ID ELISA ELISA Promoter region uration Description ID NO: EC₅₀ EC₅₀ CBA hGbin HF.T2AL Fab TAU_ITR123 2173 18.8 14.0 Fab_ext TAU_ITR124 2174 18.7 15.3 CAG — HF.T2AL Fab TAU_ITR127 2177 22.9 17.0 Fab_ext TAU_ITR128 2173 28.6 23 CBA hGbin LT2AH Fab_ext TAU_ITR129 2179 30.2 21.35 CAG — LT2AH Fab_ext TAU_ITR130 2180 23.1 18.6

Results of ELISA assays of IPN002 Fab and F(ab′)2 fragments indicate that both are able to bind wild-type and pathological tau.

Twenty-five IPN002 scFv constructs were made using one of two promoters (CBA-hGbin or CAG), alternating antibody sequence configurations (heavy-linker-light (HL) vs light-linker-heavy (LH)) and flexible G4S linkers (“G4S” disclosed as SEQ ID NO: 4535) of different lengths. The construct design is shown in Table 126 below. In the table below, the amino acid sequence of the linker are: G4S is SEQ ID NO: 4535, (G4S)2 is SEQ ID NO: 4539, (G4S)3 is SEQ ID NO: 4537, (G4S)4 is SEQ ID NO: 4540, (G4S)5 is SEQ ID NO: 4538, (G4S)6 is SEQ ID NO: 4541, and (G4S)8 is SEQ ID NO: 4542.

TABLE 126 IPN002 scFv construct design SEQ Construct Config- Construct ID No. Promoter Antibody uration Linker ID NO: 1 CBA-hGbin IPN002 HL G4S TAU_ITR131 2181 2 CBA-hGbin IPN002 HL (G4S)2 TAU_ITR132 2182 3 CBA-hGbin IPN003 HL (G4S)3 TAU_ITR133 2183 4 CBA-hGbin IPN008 HL (G4S)4 TAU_ITR134 2184 5 CBA-hGbin IPN004 HL (G4S)5 TAU_ITR135 2185 6 CBA-hGbin IPN0011 HL (G4S)6 TAU_ITR136 2186 7 CAG IPN002 HL G4S TAU_ITR137 2187 8 CAG IPN002 HL (G4S)2 TAU_ITR138 2188 9 CAG IPN003 HL (G4S)3 TAU_ITR139 2189 10 CAG IPN008 HL (G4S)4 TAU_ITR140 2190 11 CAG IPN0010 HL (G4S)5 TAU_ITR141 2191 12 CAG IPN0011 HL (G4S)6 TAU_ITR142 2192 13 CAG IPN0012 HL (G4S)8 TAU_ITR143 2193 14 CBA-hGbin IPN005 LH G4S TAU_ITR144 2194 15 CBA-hGbin IPN005 LH (G4S)2 TAU_ITR145 2195 16 CBA-hGbin IPN006 LH (G4S)3 TAU_ITR146 2196 17 CBA-hGbin IPN007 LH (G4S)4 TAU_ITR147 2197 18 CBA-hGbin IPN0012 LH (G4S)5 TAU_ITR148 2198 19 CBA-hGbin IPN0013 LH (G4S)6 TAU_ITR149 2199 20 CAG IPN004 LH G4S TAU_ITR150 2200 21 CAG IPN004 LH (G4S)2 TAU_ITR151 2201 22 CAG IPN005 LH (G4S)3 TAU_ITR152 2202 23 CAG IPN006 LH (G4S)4 TAU_ITR153 2203 24 CAG IPN007 LH (G4S)5 TAU_ITR154 2204 25 CAG IPN0014 LH (G4S)6 TAU_ITR155 2205

Viral genome constructs for IPN002 scFv expression driven by a CAG promoter (TAU_ITR137 to TAU_ITR143; SEQ ID NO: 2187-2193 and TAU_ITR150 to TAU_ITR155; SEQ ID NO: 2200-2205, in the Table above) were tested in vitro. Western blot of 293 cell supernatant demonstrated bands (25-30 kd) for each construct tested, though the bands observed for TAU_ITR137 (SEQ ID NO: 2187), TAU_ITR138 (SEQ ID NO: 2188), TAU_ITR150 (SEQ ID NO: 2200) and TAU_ITR151 (SEQ ID NO: 2201) were light and difficult to resolve. At greater exposure, bands for these constructs became more evident. CAG-promoter scFv constructs were further tested by PHF and wild-type tau ELISA. Data are shown in Table 127 below.

TABLE 127 IPN002 scFv screening results wtTau PHF Tau Construct SEQ ELISA ELISA No. Construct Description Construct ID ID NO: EC₅₀ EC₅₀ 7 CAG-IPN002-HL-G4S TAU_ITR137 2187 3.0 1.2 8 CAG-IPN002-HL-G4S2 TAU_ITR138 2188 5.4 2.1 9 CAG-IPN003-HL-G4S3 TAU_ITR139 2189 2.5 1.1 10 CAG-IPN008-HL-G4S4 TAU_ITR140 2190 3.4 3.5 11 CAG-IPN0010-HL-G4S5 TAU_ITR141 2191 7.3 7.2 12 CAG-IPN0011-HL-G4S6 TAU_ITR142 2192 8.7 20.6 20 CAG-IPN004-LH-G4S TAU_ITR150 2200 4.9 6.0 21 CAG-IPN004-LH-G4S2 TAU_ITR151 2201 8.1 5.3 22 CAG-IPN005-LH-G4S3 TAU_ITR152 2202 4.6 8.0 23 CAG-IPN006-LH-G4S4 TAU_ITR153 2203 7.2 18.7 24 CAG-IPN007-LH-G4S5 TAU_ITR154 2204 7.0 10.0 25 CAG-IPN0014-LH-G4S6 TAU_ITR155 2205 5.2 11.3

A second set of ELISA assays were conducted to compare CAG-IPN0011-HL-G4S6 and CAG-IPN0012-HL-G4S8, and these data are shown below (Table 128).

TABLE 128 IPN002 scFv screening results wtTau PHF Tau Construct SEQ ELISA ELISA No. Construct Description Construct ID ID NO: EC₅₀ EC₅₀ 12 CAG-IPN0011-HL-G4S6 TAU_ITR142 2192 9.2 3.6 13 CAG-IPN0012-HL-G4S8 TAU_ITR143 2193 8.0 4.0

Data from these studies indicate that for scFv expression, the length of the linker between the antibody chains is important and effects the expression of the IPN002 scFv. Results of the ELISA assays indicate that the expressed IPN002 scFvs bind both wild-type and PHF tau.

Viral Genomes for the Expression of PT3 Fragments

Twenty-four PT3 scFv constructs (TAU_ITR156 to TAU_ITR179: SEQ ID NO: 2206-2229) were made using one of three promoters (CAG, GFAP or synapsin), alternating PT3 antibody sequence configurations (heavy-linker-light (HL) vs light-linker-heavy (LH)) and flexible G4S linkers (“G4S” disclosed as SEQ ID NO: 4535) of different lengths. In three of these constructs, an alternate signal sequence (Glue100LP, hGhormone, pSec) was incorporated into the viral genome (TAU_ITR176 to TAU_ITR178; SEQ ID NO: 2226-2228), while in the others a heavy chain or light chain signal sequence was used. Each of the constructs included an HA tag, a rabbit globin poly(A) sequence, and 5′ and 3′ ITRs.

Expression of PT3 scFv fragments was tested in HEK293 cells followed by Western blot and binding affinity for ePHF tau of the expressed antibody was assessed by ELISA. As compared to TAU_ITR112 (SEQ ID NO: 2162; PT3-CAG-HT2AL), scFv fragments generally showed lower affinity to ePHF tau.

Eight viral genomes were designed for the expression of PT3 Fab fragments, using a CAG promoter, alternating PT3 antibody sequence configurations (heavy-linker-light (HL) vs light-linker-heavy (LH)), a T2A or F2A linker, rabbit globin poly(A) sequence, and 5′ and 3′ ITRs. As above, these constructs were tested for antibody expression in HEK293 cells followed by Western blot and for binding affinity for ePHF tau by ELISA. Each of the PT3 Fab constructs tested showed ability to bind ePHF tau.

Viral Genomes for the Expression of C10.2 Fragments

Viral genomes for expression of C10.2 fragments (Fab, F(ab′)2, scFv) were generated and tested in vitro for expression and quantitation by Western blot/ELISA and for binding affinity to ePHF tau and concentration, also by ELISA.

First, four Fab and two F(ab′)2 constructs were designed using a CAG promoter and alternating antibody sequence configurations (heavy-linker light and light-linker-heavy). A T2A linker was used in each of the six viral genomes. Expression of C10.2 antibody fragments from these viral genomes was tested in vitro in 293 cells and the supernatant collected for western blot analysis. Concentration and binding affinity for tau of C10.2 F(ab′)2 and Fab was determined by ELISA.

Next, eight C10.2 scFv constructs were prepared using a CAG promoter, alternating C10.2 antibody sequence configurations (heavy-linker-light (HL) vs light-linker-heavy (LH)) and flexible G4S linkers (“G4S” disclosed as SEQ ID NO: 4535) of different lengths. Each of the constructs further included an HA tag, a poly(A) sequence, and 5′ and 3′ ITRs. Western blot analysis of 293 cell supernatant was used to test expression of C10.2 scFv and concentration and binding affinity for tau determined by ELISA.

One viral genome (CAG-C10.2 scFv HL-G4S3) was selected for further testing of 14 different signal peptides. Each of the fourteen signal peptides was cloned into a viral genome and the viral genomes tested for expression of C10.2 scFv in vitro.

Viral genomes for cell-specific expression of C10.2 Fab, F(ab′)2 and scFv fragments were generated using GFAP or synapsin promoters. Each of the 8 scFv constructs utilized the light-linker-heavy antibody sequence configuration with flexible G4S linkers (“G4S” disclosed as SEQ ID NO: 4535) of different lengths.

Taken together, ELISA assays indicate that C10.2 F(ab′)2 fragments bind pathological tau with an affinity similar to that seen with full C10.2 antibody, whereas C10.2 Fab fragments demonstrate a reduced affinity for pathological tau.

Example 11. Identification of Antibody Epitopes

Anti-tau antibody PT3 is known to bind PHF-tau while not binding wild-type (441 amino acids: tau441; SEQ ID NO: 2127; NP_005901.2). Affinity for PHF-tau was measured at 18 pM, however, the specific epitope remains unknown, ePHF tau ELISA assay (EC₅₀ of 7.6) and SDS-PAGE showed that PT3 binds to ePHF tau.

Purified recombinant phospho-tau proteins were generated to simulate the mixture of abnormal hyperphosphorylated oligomeric tau that comprises ePHF tau and used in experiments to determine the antigen binding site for anti-tau antibody PT3. Recombinant phospho-tau proteins were phosphorylated in vitro by protein kinases Glycogen synthase kinase 3 beta (GSK3β), Protein Kinase A (PKA), Tau tubulin kinase 1 (TTBK1), Dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A), BR serine/threonine-protein kinase 2 (BRSK2), Ca²⁺/Calmodulin-dependent protein kinase II (CAMK2), BR serine/threonine-protein kinase 1 (BRSK1), Phosphorylase kinase catalytic subunit gamma 2 (PHKG2). PHF tau was used as a control. Phospho-tau ELISA assay and Western blot analyses showed that PT3 binds recombinant phospho-tau. Results indicated that PT3 bound with greatest affinity to tau protein phosphorylated by DYRK1A, as compared to those phosphorylated by other kinases.

Protein kinase DYRK1A has serine/threonine/tyrosine protein kinase activity and has been shown to play a role in regulation of cell growth, division and differentiation. DYRK1A is important in the development of the nervous system and has been identified in formation and maturation of dendritic spines. DYRK1A has been shown to be over-expressed in Down Syndrome and has been associated with early onset of AD-type pathology, Down Syndrome and Autism Spectrum Disorders. Previous studies (Wegiel, J. et al., 2011, FEBS J 278(2):236-45, the contents of which are herein incorporated by reference in their entirety) indicate that DYRK1A phosphorylates human tau at 11 threonine (pThr) and serine (pSer) sites.

Tau441 was incubated in vitro with DYRK1A for 0, 5, 10, 20, 45, 82 or 120 minutes and then analyzed by western blot using PT3. Binding of PT3 to phospho-tau was increased with each increase in incubation time, with the greatest binding evident at 120 minutes.

Twelve recombinant tau mutant proteins were generated, based on phosphorylation sites of Tau441 by DYRK1A, having mutations at T181, S199, S202, T205, T212, T217, T231, S396, S400, S404 and S422. Amino acids at these positions were mutated to Alanine and a his tag was added as a tag or selectable marker.

Western blot of the 12 tau441 mutants and wild-type tau441 using anti-tau antibody PT3 showed no binding to recombinant tau proteins with mutations at T212 or T217, even though western blot using anti-his antibody showed recombinant tau441 protein present in each of these lanes. Semi-quantitative analyses of these western blots indicated substantially equivalent recombinant tau protein present based on anti-his staining. PT3 binding was more variable with greatest signal for recombinant tau 441 with a mutation at S422. Further quantification of PT3 signal normalized to anti-his signal indicated greatest binding of PT3 to recombinant tau441 with a mutation at S199 and then with decreasing binding for each of recombinant tau441 proteins with mutations at S422, T205, S400, S404, T181, S396, T231, wild-type tau441, S202, respectively.

ELISA was performed using PT3 as the immobilized antibody and DYRK1A phosphorylated tau proteins or recombinant tau mutant proteins in the applied solution (333 ng/mL). Data are shown in Table 129 below.

TABLE 129 PT3, Tau and Tau mutant ELISA Tau variant OD450-570 Phospho_Tau441 0.5 Tau441 0.0 Phospho_Tau441_T212A 0.0 Tau441_T212A 0.0 Phospho_Tau441_T202A 0.6 Tau441_T202A 0.0 Phospho_Tau441_S404A 0.6 Tau441_S404A 0.0 Phospho_Tau441_T181A 0.4 Tau441_T181A 0.0 Phospho_Tau441_S199A 0.7 Tau441_S199A 0.0 Phospho_Tau441_T205A 0.4 Tau441_T205A 0.0 Phospho_Tau441_T217A 0.0 Tau441_T217A 0.0 Phospho_Tau441_T231A 0.3 Tau441_T231A 0.0 Phospho_Tau441_S396A 0.5 Tau441_S396A 0.0 Phospho_Tau441_S400A 0.3 Tau441_S400A 0.0 Phospho_Tau441_S422A 0.3 Tau441_S422A 0.1

As by western blot analysis, results again indicated poor binding of anti-tau antibody PT3 to tau with mutations at T212 or T217.

Six additional recombinant tau mutant proteins were generated to further elucidate the PT3 epitope (tau441−S214A, tau441−T212A+S214A, tau441−T212A+T217A, tau441−T217A+T231A, tau441−T212A+T231A, tau441−T212A+T217A+T231A). Western blot of these six additional tau441 mutants and wild type tau441 using PT3 showed no binding to recombinant tau proteins with mutations at T212 or T217, even though western blot using anti-his antibody showed recombinant tau441 protein present in each of these lanes.

PT3 ELISA using 210 ng/mL of phospho-Tau variants gave results as shown in the Table below (see Table 130) and confirmed the findings of the western blot analyses, wherein binding of PT3 was eliminated with recombinant tau proteins with mutations at T212 or T217.

TABLE 130 PT3 and phosphoTau ELISA Tau variant OD450-570 Wild-type Tau441 1.7 Tau441-T212A 0.0 Tau441-S214A 1.5 Tau441-T217A 0.0 Tau441-T231A 2.0 Tau441-T212A + S214A 0.1 Tau441-T212A + T217A 0.0 Tau441-T217A + T231A 0.1 Tau441-T212A + T231A 0.1 Tau441-T212A + T217A + T231A 0.0 Tau441_no phos 0.0 Tau441-T212A-no phos 0.0

A series of nine new phospho-tau peptides were synthesized as indicated in Table 131 below, where “p” indicates a phosphorylation site and tested by PT3 ELISA.

TABLE 131 Phospho Tau Peptides SEQ Tau ID ID Description Sequence NO: EC₅₀ Tau1 pT212 SPGTPGSRSRpTPSLP 2128 — TPP Tau2 pT217 SRTPSLPpTPPTREPK 2129 17.8 Tau3 pT231 KKVAVVRpTPPKSPSS 2130 — Tau4 pT212 +  TPGSRSRpTPSLPpTP 2131 13.6 pT217 PTREPK Tau5 pT217 +  SRTPSLPpTPPTREPK 2132 15.6 pT231 KVAVVRpTPPKSPSS Tau6 pT212 +  TPGSRSRpTPSLPpTP 2133 12.0 pT217 + PTREPKKVAVVRpTPP pT231 KSPSS Tau7 wt tau TPGSRSRTPSLPTPPT 2134 — REPKKVAVVRTPPKSP SS Tau8 pT212 +  TPGSRSRpTPSLPTPP 2135 — pT231 TREPKKVAVVRpTPPK SPSS Tau9 wt tau TPPSSGEPPKSGDRSG 2136 — YSSPGSPGTPGSRSRT PSLPTPPTREPKKVAV V

Further analysis of the Tau1 peptide by PT3 or AT100 ELISA or ELISA using a series of pT212 commercial antibodies confirmed that the Tau1 peptide was indeed phosphorylated at pT212.

Together, the data above indicate that PT3 binds tau phosphorylated at two sites, pT212 and pT217. A follow-up PT3 ELISA using peptides Tau1 (pT212), Tau2 (pT217), Tau4 (pT212+pT217) and Tau7 (wt tau) yielded EC₅₀ values of 83.6 and 17.2 for Tau2 (pT217) and Tau4 (pT212+pT217) peptides respectively. A PT3 competition ELISA using Tau1-6, Tau9 and DYRK1A phosphorylated Tau441 supported these findings. Based on these findings, a hypothetical model of PT3 binding was developed, wherein PT3 binds pT212 tau very weakly and pT217 with greater affinity (approximately 1,000× stronger). Tau phosphorylated at both pT212 and pT217 shows the greatest binding by PT3, with an affinity higher than that of PT3 to either phospho-site on its own. It was noted that PT3 binds wild type tau441 weakly as well.

Example 12. Engineering of Antibody Variants Intrabodies

Viral genomes for expressing anti-tau intrabodies are engineered to test the effect of intracellular antibody expression. Secretory signal peptides are removed to retain the intrabody within the cell. Constructs are tested with the assays (ELISA and Western blot) described above. Intrabodies are not expected to be present in the cell supernatant, but are expected to be abundant in the cell lysate.

Nanobodies

Viral genomes for expressing anti-tau nanobodies are developed and tested using the assays described above. Nanobodies may demonstrate better permeability in tissues, greater stability, higher solubility, shorter plasma half-life, and enhanced binding to hidden targets.

Bispecific Antibodies

Viral genomes for expressing bispecific antibodies, bispecific nanobodies or bispecific scFvs are engineered and tested using the assays described above or any appropriate qualitative or quantitative assay known to one with skill in the art.

Example 13. Intramuscular Expression of Antibodies Engineering for Enhanced Muscle Tropism

AAV particles comprising viral genomes encoding anti-tau antibodies are modified for enhanced transduction to muscular tissue. The AAV capsid is engineered to increase tropism to muscle. In one embodiment, AAV9 is modified to increase muscle tropism. In another embodiment, AAV2 and/or AAV3 are modified to increase muscle tropism. AAV particles may be delivered directly to muscle via intramuscular delivery or may be administered systemically, but still target muscular tissues.

In Vivo Intramuscular Dosing Studies for Expression of Anti-Tau Antibodies

AAV1, AAV2 or VOY101 AAV particles comprising viral genomes encoding an anti-tau antibody (e.g., IPN002, PT3, C10.2, PHF1, MC1, CP13) are provided to subject (e.g., mouse, rat, rabbit, guinea pig, pig, ferret, dog, cat, non-human primate, or human) in a single intramuscular dose or in three intramuscular doses (1e12, 3e11, or 1e11) to the gastrocnemius muscle at a volume of 30-50 μL/site. The AAV particles will be formulated in PBS with 0.001% F-68. The subject may be wild-type, diseased, or model a disease or indication. Serum, CSF and/or tissue samples (hippocampus, cortex, thalamus, brain stem, spinal cord, liver, skeletal muscle) are collected for quantification of anti-tau antibody levels, with repeated sample collection for monitoring antibody presence over time. Serum will be collected at −2, 7, 14, 21, 28, 35, 42 and 43 days, as counted from day of administration of AAV particles, passive immunization or control composition. Antibody levels will be quantified using Tau-ELISA or ePHF ELISA, as described above. It is expected that administration of AAV particles, especially at the highest dose, will lead to detectable IPN002 antibody expression in serum samples. Vector genome quantification will be determined for a subset of tissues, such as for muscle, brain, and/or peripheral tissue (e.g., liver). Passive immunization with an anti-tau antibody (60 mg/kg) will be used as a control. Study designs are shown in Tables 132 and 133 below.

TABLE 132 AAV1.IPN002 IM study design SEQ End Construct TAU_ITR ID Dose Dose of Configuration ID NO: μL (vg/kg) (vg) Route N study CAG-IPN002- TAU_ITR1 1990 4 × 40 5E13 1E12 IM 6 D 43 HF.T2AL CAG-IPN002- TAU_ITR1 1990 2 × 40 1.5E13  3E11 IM 6 D 43 HF.T2AL CAG-IPN002- TAU_ITR1 1990 1 × 40 5E12 1E11 IM 6 D 43 HF.T2AL Passive — — 60 — i.p. 6 D 43 immunization mg/kg with IPN002 weekly PBS with — — 100 — — IM 4 D 43 0.001% F-68

TABLE 133 AAV2.IPN002 IM study design SEQ End Construct TAU_ITR ID Dose Dose of Configuration ID NO: μL (vg/kg) (vg) Route N study CAG-IPN002-HF.T2AL TAU_ITR1 1990 4 × 40 4E13 8E11 IM 6 D 43 CAG-IPN002-HF.T2AL TAU_ITR1 1990 2 × 40 1.5E13  3E11 IM 6 D 43 CAG-IPN002-HF.T2AL TAU_ITR1 1990 1 × 40 5E12 1E11 IM 6 D 43

Secondary readouts include cage-side observations for the first week and weekly body weight checks. No adverse side effects are anticipated.

Example 14. Intramuscular Dosing of Anti-Tau Antibody AAV Particles

To assess anti-tau antibody levels in serum, CSF or CNS tissue of mice after bilateral intramuscular delivery of vector, a viral genome (TAU_ITR112; SEQ ID NO: 2162; PT3-CAG-HT2AL) was packaged into AAV1, AAV2 or VOY101 capsids. AAV particles were formulated in PBS with 0.001% F-68 and provided at a dose of 4.65×10¹³ vg/kg across four intramuscular injection sites in the gastrocnemius and thigh muscle of C57Bl/6 mice. Forty-two days after administration, mice were sacrificed by intracardiac perfusion and CSF and/or tissue samples (hippocampus, cortex, thalamus, brain stem, spinal cord, olfactory bulb, liver, skeletal muscle) were collected for analysis. Serum samples were collected at −2, 7, 14, 21, 28, 35, 42 and 43 days, as counted from day of administration of AAV particles, passive immunization or vehicle control (PBS and 0.001% F-68). Passive immunization with an anti-tau antibody (30 mg/kg) was used as a control. Study design is shown in Table 134 below.

TABLE 134 PT3 IM study design SEQ End TAU_ITR ID Dose Dose of AAV Particle ID NO: μL (vg/kg) (vg) Route N study AAV1.CAG-PT3-HF.T2A L TAU_ITR112 2162 4 × 40 4.65E13 1E12 IM 8 D 43 AAV2.CAG-PT3-HF.T2AL TAU_ITR112 2162 4 × 40 4.65E13 1E12 IM 8 D 43 VOY101.CAG-PT3-HF.T2AL TAU_ITR112 2162 4 × 40 4.65E13 1E11 IM 8 D 43 Passive immunization with — — 30 — i.p. 8 D 43 PT3 mg/kg weekly PBS with 0.001% F-68 — — 100 — — IM 4 D 43

Vector genome quantification was determined for a subset of tissues, such as for muscle (injection/non-injection sites), brain, and/or peripheral tissue (e.g., liver) by droplet digital PCR and normalized per diploid cell (VG/DC). Antibody levels in the hippocampus, cortex, spinal cord, liver, serum, gastrocnemius and CSF were quantified using ePHF ELISA, as described above. Secondary readouts included cage-side observations for one week after AAV particle administration and weekly body weight measurements. Vector genome biodistribution quantifications (VG/DC) are shown in Table 135 below.

TABLE 135 Vector genome quantification of ssVOY101.PT3 constructs Passive Vehicle AAV1.PT3 AAV2.PT3 VOY101.PT3 Immunization (PBS) Hippocampus 0.1 0.3 8.6 0.0 0.0 Cortex 0.1 0.0 14.8 0.0 0.0 Olfactory Bulb 0.0 0.0 11.5 0.0 0.0 Thalamus 0.2 0.0 21.7 0.0 0.0 Brainstem 0.2 0.0 19.1 0.0 0.0 Spinal Cord 0.3 0.0 10.9 0.0 0.0 Gastrocnemius 61.0 27.5 6.7 0.0 0.0 Left Bicep 1.0 8.4 0.3 0.0 0.0 Right Thigh 71.3 8.9 4.2 0.0 0.0 Spleen 2.8 1.9 1.0 0.0 0.0 Liver 12.6 0.1 1.8 0.0 0.0

Subsequent to bilateral intramuscular delivery of TAU_ITR112 (SEQ ID NO: 2162; PT3-CAG-HT2AL) in AAV1, AAV2 or VOY101 very low biodistribution in CNS tissues was observed with AAV1 and AAV2 vectors. VOY101.PT3 showed higher viral genome levels per diploid cell across all tested CNS tissues.

In peripheral tissues, AAV1, AAV2 and VOY101 delivery of PT3 resulted in detectable biodistribution at the site of the injection (gastrocnemius and thigh skeletal muscle), but presence of viral genomes in distant tissues from the injection site (e.g., left bicep), was scare. In skeletal muscle, AAV1 particles showed a trend for increased biodistribution as compared to AAV2 and VOY101, after IM administration. Viral genome quantifications indicate that, in gastrocnemius and thigh tissue, AAV1 was the most efficient at delivering PT3 encoding viral genomes, while VOY101 was least efficient in these peripheral tissues.

ePHF ELISA was used to assess PT3 antibody expression in tissues collected after IM injection of AAV1, AAV2, or VOY101 particles. Samples of hippocampus, cortex, spinal cord, serum, liver and gastrocnemius were analyzed. Data are shown in Table 136 below as ng/mg protein.

TABLE 136 PT3 expression from AAV1, AAV2, or VOY101 particles (ng/mg protein) Passive Vehicle AAV1.PT3 AAV2.PT3 VOY101.PT3 Immunization (PBS) ng/mg ng/mg ng/mg ng/mg ng/mg Hippocampus 3.9 0.0 47.3 0.0 0.0 Cortex 1.6 0.0 104.9 0.0 0.0 Spinal Cord 0.0 0.0 27.6 0.5 0.0 Liver 165.0 34.6 56.8 24.3 0.0 Gastrocnemius 1233.0 353.0 563.7 58.0 0.0 Serum (μg/mL) 1900.0 247.5 689.0 315.0 0.0

Based on PT3 antibody expression quantification as determined by ePHF ELISA, VOY101 was the only one of the three capsids to deliver detectable levels of PT3 to tissues of the CNS after IM dosing. Passive immunization and administration of vehicle resulted in substantially no detectable PT3 expression in tissue collected from the hippocampus, cortex and spinal cord. In peripheral tissues, PT3 antibody expression was detectable in liver and injected muscle (gastrocnemius) in all groups, other than vehicle, with the highest expression seen with delivery using AAV1, followed by VOY101 and AAV2, respectively. These results are consistent with the vector genome quantification (VG/DC) determined by ddPCR, above.

In serum collected on the terminal day, quantification of PT3 antibody expression demonstrated enhanced expression of PT3 when delivered with AAV1, as compared to AAV2, VOY101 and passive immunization. Whilst not wishing to be bound by theory, one might have expected approximately 200-400 μg/mL of antibody to be present in the serum of mice dosed with 30 mg/kg. In serum samples collected prior to the terminal day (at days 7, 14, 21, 28, 35, and 42 days), an abundance of PT3 antibody was detected in each of the samples and these levels were largely sustained throughout the entirety of the experiment. PT3 antibody levels in serum, delivered by AAV1 and VOY101 were higher than antibody levels evident after passive immunization, while AAV2 delivery of PT3 encoding viral genomes resulted in PT3 antibody levels in serum similar to those seen with passive immunization.

Cerebrospinal fluid samples collected on the terminal day were also assessed for PT3 expression after IM delivery with one of AAV1, AAV2, VOY101 or passive immunization. When delivered by passive immunization, PT3 antibody levels in the CSF were approximately 0.05% of the levels seen in serum samples. Whilst not wishing to be bound by theory, this finding is consistent with what might be expected by one with skill in the art. Data for PT3 antibody expression in CSF and serum samples is shown in Table 137 below.

TABLE 137 PT3 expression from AAV1, AAV2, or VOY101 particles (ng/mg protein) Passive Vehicle AAV1.PT3 AAV2.PT3 VOY101.PT3 Immunization (PBS) ng/mg ng/mg ng/mg ng/mg ng/mg Serum (μg/mL) 2471.0 229.0 689.0 342.0 0.0 CSF (ng/mL) 851.0 174.8 886.0 157.5 0.0 % CSF/Serum 0.0 0.1 0.1 0.0 0.0

PT3 antibody expression in CSF was highest when delivered by AAV1 or VOY101, followed by AAV2 and passive immunization. Vectored delivery, regardless of capsid, resulted in greater CSF PT3 antibody expression than seen with passive immunization.

Taken together, these data indicate that intramuscular delivery of VOY101 can result in antibody expression in CNS tissues, while use of AAV1 leads to higher expression of antibody in peripheral tissues.

Example 15. Evaluation of Anti-Tau Antibody Constructs in Non-Human Primates

Adult Rhesus macaque monkeys, pre-screened for low anti-AAV antibody levels, will receive intraparenchymal (IPa; e.g., thalamus and/or putamen), intracisternal (CM), intravenous (IV) or intramuscular (IM) administration of anti-tau antibody AAV particles to assess expression, distribution and therapeutic potential.

Anti-tau antibody AAV particles will be formulated in a solution comprising 180 mM sodium chloride, 10 mM sodium phosphate, and 0.001% Pluronic Acid. Dosing concentrations will be determined based on route of administration. For IPa administration, two animals will each receive bilateral infusions into two brain regions (e.g., the thalamus and putamen) by convection enhanced delivery device guided by MRI. An additional three animals will each receive a single 1 mL bolus injection into the CSF via the cisterna magna. Intravenous administration will be delivered via injection to the saphenous vein, or other readily accessible vein of the superior leg. Intramuscular injections will be administered in at least one, but up to four sites, of the same or of different muscles, such as the gastrocnemius muscle. One group of animals will receive passive immunization with the antibody constructs of interest. Animals will be monitored post-injection(s) for 28 days, with weekly body weight measurements and daily cage-side behavioral, mortality and morbidity checks serving as secondary readouts. Serum and CSF samples will be collected pre-dose and prior to necropsy.

On day 29, animals will be transcardially perfused with PBS, tissues will be collected and drop fixed in paraformaldehyde for histological analyses or flash frozen for biochemical assay. Tissues processed for histological analysis will be sectioned and immunostained with HRP-labeled mouse IgG1 for presence of tau antibodies. Further, these samples will be co-immunostained with NeuN, Iba1 or GFAP to identify cell-type. Samples snap frozen for biochemical analyses will be utilized for PCR to detect vector genomes and mRNA, ELISA to detect antibodies and MS to determine protein levels. Blood and CSF samples will be assessed for antibody and AAV levels.

Example 16. Treatment of Tau-Associated Disease

AAV particles comprising viral genomes for delivery of an anti-tau antibody or fragment thereof are administered to a patient who has been diagnosed with a tau associated disease, disorder or condition. The purpose of the treatment may be aimed to manage the disease, prevent or slow the progression of the disease, treat the symptoms associated with the disease and/or cure the disease.

The AAV particles are administered to a subject by IM, IV, ICV, IPa or IT administration. The administration may include one or more injections over a period of time. The level and distribution of AAV particles and antibody expression is monitored by standard diagnostic techniques known in the art. Such diagnostic techniques include e.g. (e.g. from blood, urine, or saliva), cerebrospinal fluid (CSF) testing, or any other testing useful for monitoring antibody levels in the body.

Additionally, the progression of the disease and the health of the patient is monitored by standard diagnostic techniques known in the art. Such techniques may include diagnostic imaging (e.g. X-ray, MRI scans, Ultrasound scans, PET scans, Nuclear scans, mammography), biopsy, laboratory tests (e.g. from blood, urine, or saliva), cerebrospinal fluid (CSF) testing, vital signs, clinical tests (cognitive, motor or reflex tests) and other relevant techniques. Treatment with the AAV particles may result in cure of the tau-associated disease, slowing down or stabilizing the progression of the disease, or have no effect on the progression of the disease. Additionally, the treatment may reduce severity of one or more symptoms associated with the disease, eliminate one or more symptoms associated with the disease or have no effect on the symptoms.

Example 17. Affinity of a Panel of Anti-Tau Antibodies to ePHF or Wild-Type Tau

A panel of eight BioLegend (San Diego, Calif.) monoclonal murine anti-tau antibodies were tested for their affinity to ePHF tau and wild-type tau (Tau441), using an ELISA assay as described in Example 4 (Tau441 immobilized on the 96-well plate for the wild-type tau assay, instead of ePHF tau). The panel of BioLegend antibodies included clones Tau5 (anti-tau, 210-230; cat #806401), Tau12 (anti-tau, 6-18; cat #806501), Tau46 (anti-tau, 404-421; cat #806601), 43D (anti-tau, 1-100; cat #816601), 2G9.F10 (anti-tau, 157-168; cat #824601), PHF-6 (anti-tau phospho Th231; cat #828901), PHF-13 (anti-tau phospho Ser396; cat #829001) and Tau-13 (anti-tau, 20-35; cat #835201), with PHF-1 used as a control antibody.

As described above, the ePHF were first immobilized on a 96-well plate overnight by pre-coating with 1500× of the concentrated PHF tau at 4° C., washed 3 times with PBS then blocked with 3% BSA for 2 hrs at room temperature or overnight at 4° C. Anti-tau antibodies were diluted in 3% BSA and loaded onto the plates. Plates were then incubated for 2 hrs at room temperature. Wells were washed 5 times with TBS/0.5% Tween 20 wash buffer, then incubated with 1:5000 dilution of anti-mouse antibody labeled with HRP (Thermo Fisher Scientific, Waltham, Mass.) for 30 min. Plates were then developed by incubating with one-step TMB substrate (Thermo Fisher Scientific, Waltham. Mass.) for 30 min. stopped by 2N H₂SO₄ and read using a BioTek Synergy H1 hybrid reader (BioTek, Winooski, Vt.) at 450 nm. The concentration of anti-tau antibodies, and their affinity for ePHF tau, was determined using a standard curve. The data are shown in Table 138 below.

TABLE 138 BioLegend antibody PHF Tan ELISA (OD450 data) ng/ML Tau5 Tau12 Tau46 43D 2G9.F10 PHF-6 PHF-13 Tau-13 PHF-1 1000.0 3.2 3.2 3.2 3.1 2.8 2.9 3.2 3.1 3.1 3.1 3.2 3.1 1.9 2.0 3.2 3.2 2.1 2.2 333.3 3.2 3.2 3.2 3.1 2.3 2.6 3.2 3.1 2.9 3.0 3.0 3.1 1.2 1.2 3.2 3.2 1.5 1.6 111.1 3.2 3.2 3.2 3.2 1.7 2.0 3.2 3.2 2.4 2.8 2.7 2.9 0.6 0.7 3.2 3.2 1.2 1.3 37.0 2.6 2.9 3.2 3.2 0.9 1.0 3.2 3.2 1.6 2.0 1.9 2.3 0.3 0.3 3.2 3.2 0.8 0.9 12.3 1.7 2.1 3.2 3.2 0.4 0.4 3.0 3.1 0.7 0.9 1.1 1.3 0.1 0.1 2.8 3.1 0.5 0.5 4.1 0.8 0.9 2.2 2.4 0.2 0.1 1.7 1.9 0.3 0.3 0.4 0.5 0.1 0.0 1.4 1.8 0.2 0.2 1.4 0.4 0.4 1.0 1.0 0.1 0.0 0.7 0.8 0.1 0.1 0.2 0.2 0.0 0.0 0.6 0.7 0.1 0.1 0.5 0.1 0.1 0.4 0.4 0.0 0.0 0.3 0.3 0.0 0.0 0.1 0.0 0.0 0.0 0.2 0.2 0.1 0.1

PHF-13 showed the lowest affinity for ePHF tau, while all other BioLegend antibodies demonstrated greater affinity for ePHF tau than control antibody PHF-1. EC₅₀ values are shown in Table 139 below.

TABLE 139 EC₅₀ values for anti-tau antibodies Antibody EC₅₀ Tau5 9.3 Tau12 2.2 Tau46 79 43D 3.3 2G9.F10 29.2 PHF-6 20 PHF-13 36542 Tau-13 4.1 PHF-1 1888

The same panel of antibodies was then tested for affinity to wild-type tau (Tau441) using an ELISA assay in which Tau441 was immobilized to the plate instead of ePHF tau as described above. All other aspects of the assay remained the same. OD450 and EC₅₀ data are shown in Tables 140 and 141 below. Phospho-tau specific antibodies PHF-6, PHF-13 and PHF-1 showed little to no affinity to Tau441, as expected.

TABLE 140 BioLegend antibody Tan 441 ELISA (OD450 data) Ng/ML Tau5 Tau12 Tau46 43D 2G9.F10 PHF-6 PHF-13 Tau-13 PHF-1 1000.0 3.3 3.3 3.2 3.2 2.2 0.1 0.1 3.2 0.1 333.3 3.3 3.3 3.2 3.3 1.6 0.0 0.1 3.2 0.1 111.1 3.3 3.3 3.0 3.2 0.9 0.0 0.1 3.1 0.1 37.0 2.6 3.1 2.0 3.0 0.5 0.0 0.0 2.3 0.1 12.3 1.2 2.0 1.0 2.0 0.2 0.0 0.1 1.2 0.1 4.1 0.6 0.9 0.4 0.9 0.1 0.0 0.0 0.5 0.1 1.4 0.2 0.4 0.2 0.4 0.1 0.1 0.0 0.2 0.1 0.0 0.1 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.1

TABLE 141 EC₅₀ values for anti-tau antibodies Antibody EC₅₀ Tau5 18.1 Tau12 8.5 Tau46 25.5 43D 9.0 2G9.F10 235.3 PHF-6 1.9 PHF-13 481.8 Tau-13 18.9 PHF-1 1.4

Example 18. Vectorized PT3 and IPN002 Expression in Primary Hippocampal Neurons

Primary neuronal cultures were used to test cell specificity, transduction efficiency and expression of PT3 & IPN002 using viral genomes listed in Table 142, encapsulated in Voy101. For preparation of primary cultures, brain tissue was removed from CDI mice at embryonic day 17 (E17) and meninges removed. The hippocampi and cortices were dissected out and digested with papain. Cells were counted and plated (17,500 cells/well) accordingly.

On day 4, in vitro (DIV4), cells were transduced with (3E6, 1E6, 3.33E5, 1.11E5, 3.7E4 VG/cell) AAV particles comprising the PT3 or IPN002 encoding viral genomes or VOY101-GFP as a positive control. Untransduced neurons served as the negative control.

Constructs shown in Table 142 with PT3 or IPN002 expression driven by ubiquitous or cell-type specific promoters were tested.

TABLE 142 PT3 & IPN002 Constructs for in vitro testing in primary cultures SEQ Construct ID ID NO: Configuration TAU_ITR104 2154 CAG PT3 F2a HL TAU_ITR108 2158 CAG PTS F2a LH TAU_ITR112 2162 CAG PT3 T2A HL TAU_ITR116 2166 CAG PT3 T2a LH TAU_ITR103 2153 CBA PT3 F2a HL TAU_ITR107 2157 CBA PT3 F2a LH TAU_ITR111 2161 CBA PT3 T2A HL TAU_ITR115 2165 CBA PT3 T2a LH TAU_ITR105 2155 GFAP PT3 F2a HL TAU_ITR109 2159 GFAP PT3 F2A LH TAU_ITR113 2163 GFAP PT3 T2A HL TAU_ITR117 2167 GFAP PT3 T2A LH TAU_ITR106 2156 Syn PT3 F2a HL TAU_ITR110 2160 Syn PT3 F2a LH TAU_ITR114 2164 Syn PT3 T2A HL TAU_ITR118 2168 Syn PT3 T2a LH TAU_ITR1 1990 CAG.IPN002.HC.T2A.LC TAU_ITR10 1999 CAG.IPN002.LC.T2A.HC TAU_ITR4 1993 CBA.IPN002.HC.T2A.LC TAU_ITR87 2137 CBA.IPN002.LC.T2A.HC TAU_ITR2 1991 CAG.IPN002.HC.F2A.LC TAU_ITR9 1998 CAG.IPN002.LC.F2A.HC TAU_ITR3 1992 CBA.IPN002.HC.F2A.LC TAU_ITR11 2000 CBA.IPN002.LC.F2A.HC

Cultures were confirmed to be approximately 60-70% neuronal as measured by NeuN staining. On DIV7, cells were fixed in 4% paraformaldehyde and 4% sucrose in PBS for 15 minutes followed by four PBS washes and used for immunocytochemical experiments. Cells were blocked with 3% BSA and 0.05% saponin in PBS for 1 hour at room temperature. Cells were stained with primary antibodies for IgG, GFAP, and NeuN and incubated overnight at 4 C in blocking buffer, then washed with four PBS washes. Cells were stained in secondary antibodies (1:1000 in blocking buffer) and incubated for 1 hour at room temperature followed by four washes in PBS. Höechst was applied at 1:1000 in PBS at room temperature for 15 minutes to stain nuclei, then washed four times with PBS. Imaging was performed using a BioTek Cytation 5. When transduced at 1E4 to 3E6 vg/cell, viral genomes comprising a GFAP-promoter, namely TAU_ITR109 (SEQ ID NO: 2159) TAU_ITR113 (SEQ ID NO:2163): TAU_ITR117 (SEQ ID NO: 2167) showed exclusive expression in GFAP positive astrocytes whereas viral genomes comprising a synapsin promoter, namely TAU_ITR106 (SEQ ID NO: 2156); TAU_ITR110 (SEQ ID NO: 2160); TAU_ITR114 (SEQ ID NO: 2164); TAU_ITR118 (SEQ ID NO: 2168), showed exclusive expression in NeuN positive neurons.

The percentage PT3 positive cells obtained by immunocytochemistry are shown in Table 143.

TABLE 143 % PT3 positive cells Vg/cell ITR ID 3.33E+05 1.00E+06 3.00E+06 TAU_ITR104 51.15 71.58 52.4 56.31 69.06 57.72 TAU_ITR108 60.94 73.51 81.1 57.39 73.21 77.94 TAU_ITR112 78.7 66.12 55.97 62.31 57.62 59.5 TAU_ITR116 30.28 52.03 71.06 25.12 55.21 61.07 TAU_ITR103 42.05 58.82 69.26 53.65 64.46 68.38 TAU_ITR107 31.7 51.4 82.18 35.18 56.07 69.55 TAU_ITR111 52.14 60.63 74.48 56.23 59.93 51.03 TAU_ITR115 22.54 45.92 57.17 20 43.56 47.05

Among the CAG and CBA promoter driven constructs, higher percentage of PT3 positive cells was observed when the vg/cell concentration was increased. Some variations in the percentage PT3 positive cells was observed at the 3.33E+05 vg/cell concentration. But higher vg/cell concentrations showed similar % PT3 cells across the different constructs.

The percentage IPN002 positive cells obtained by immunocytochemistry are shown in Table 144.

TABLE 144 % IPN002 positive cells (ng/ml) Vg/cell ITR ID 3.33E+05 1.00E+06 3.00E+06 TAU_ITR1 25.17 38.95 56.4 (CAG.IPN002.HC.T2A.LC) 22 31 55.16 TAU_ITR10 7.66 23.36 40.83 (CAG.IPN002.LC.T2A.HC) 7.33 20.96 35.51 TAU_ITR2 1.31 9.72 21.45 (CAG.IPN002.HC.F2A.LC) 0.64 6.62 17.65 TAU_ITR9 4.85 16.4 27.13 (CAG.IPN002.LC.F2A.HC) 3.34 13.42 26.57 TAU_ITR4 10.82 23.65 38.77 (CBA.IPN002.HC.T2A.LC) 9.01 21.59 31.08 TAU_ITR87 1.9 7.85 21.61 (CBA.IPN002.LC.T2A.HC) 1.38 6.34 15.31 TAU_ITR3 3.2 7.94 20.58 (CBA.IPN002.HC.F2A.LC) 2.65 6.33 17.48 TAU_ITR11 5.45 14.96 23.64 (CBA.IPN002.LC.F2A.HC) 3.49 10.49 20.4

Among the CAG and CBA promoter driven constructs, higher percentage of IPN002 positive cells was observed when the vg/cell concentration was increased. Some variations in the percentage PT3 positive cells was observed at the 3.33E+05 vg/cell concentration. In all three vg/cell concentrations tested TAU_ITR1 (CAG.IPN002.HC.T2A.LC) showed the highest percentage of IPN002 expression.

The supernatant collected on DIV7 (3 days after transduction) was used along with IgG1 mouse uncoated ELISA kit (ThermoFisher) for quantification of antibody/mL (ms IgG ng/mL). Comparison between the CAG promoter driven constructs (TAU_ITR112, TAU_ITR116, TAU_ITR104, TAU_ITR108) and CBA promoter driven constructs (TAU_ITR111, TAU_ITR115, TAU_ITR103, TAU_ITR107) comprising either a T2A cleavage site or F2A cleavage site showed that the CBA promoter provides more robust expression of PT3 when combined with T2A, as compared to CBA promoter driven PT3 expression combined with a T2A cleavage site. Further, viral genomes comprising a CAG or CBA promoter and a T2A cleavage site provided more robust PT3 expression than viral genomes comprising an F2A linker.

PT3 expression data are shown in Table 145.

TABLE 145 PT3 expression Vg/cell ITR ID 3.33E+05 1.00E+06 3.00E+06 TAU_ITR104 7.69 8.578 7.29 7.657 8.289 6.681 TAU_ITR108 10.03 11.05 12.58 9.30 12.30 13.79 TAU_ITR112 39.92 30.24 22.68 37.07 29.00 21.74 TAU_ITR116 17.16 28.18 34.44 19.14 27.62 37.22 TAU_ITR103 8.55 9.65 7.56 7.18 11.58 9.23 TAU_ITR107 6.32 9.02 9.06 7.21 9.04 8.92 TAU_ITR111 31.16 29.70 30.65 34.09 39.55 38.47 TAU_ITR115 14.70 20.02 21.02 17.12 22.13 24.07

Among the constructs tested, TAU_ITR112 (CAG PT3 T2A HL), TAU_ITR111 (CBA PT3 T2A HL) with T2A.HL format showed comparatively higher PT3 expression levels than the other constructs tested. TAU_ITR115 with CBA PT3 T2A LH also showed high PT3 expression at the 1.00E+06 vg/cell concentration.

The PT3 expression (ng/ml) in primary hippocampal neurons when comprising a T2A cleavage site was higher than when an F2A cleavage site was used. A similar observation was made in vivo in the hippocampus and CSF of mice transduced with AAV particles comprising PT3 encoding viral genomes.

As a comparison, PT3 expression levels obtained by ELISA were compared to IPN002 antibody expression levels (ng/ml) and are shown in Table 146.

TABLE 146 IPN002 expression (ng/ml) Vg/cell ITR ID 3.33E+05 1.00E+06 3.00E+06 TAU_ITR1 25.17 38.95 56.4 (CAG.IPN002.HC.T2A.LC) 22 31 55.16 TAU_ITR10 7.66 23.36 40.83 (CAG.IPN002.LC.T2A.HC) 7.33 20.96 35.51 TAU_ITR2 1.31 9.72 21.45 (CAG.IPN002.HC.F2A.LC) 0.64 6.62 17.65 TAU_ITR9 4.85 16.4 27.13 (CAG.IPN002.LC.F2A.HC) 3.34 13.42 26.57 TAU_ITR4 10.82 23.65 38.77 (CBA.IPN002.HC.T2A.LC) 9.01 21.59 31.08 TAU_ITR87 1.9 7.85 21.61 (CBA.IPN002.LC.T2A.HC) 1.38 6.34 15.31 TAU_ITR3 3.2 7.94 20.58 (CBA.IPN002.HC.F2A.LC) 2.65 6.33 17.48 TAU_ITR11 5.45 14.96 23.64 (CBA.IPN002.LC.F2A.HC) 3.49 10.49 20.4

In general, an increase in vg/cell concentrations resulted in higher IPN002 expression levels. The CAG promoter based constructs showed higher IPN002 expression when compared to CBA promoter driven expression.

The IPN002 expression (ng/ml) in primary hippocampal neurons when comprising a T2A cleavage site was higher than when an F2A cleavage site was used. A similar observation was made in vivo in the hippocampus and CSF of mice transduced with AAV particles comprising the IPN002 encoding viral genomes.

Taken together these data suggest that viral genomes comprising a T2A cleavage site may contribute to greater antibody expression than when an F2A cleavage site is used.

Example 19. Expression and Distribution of scFv Based Anti-Tau Antibody Constructs

Testing of IPN002 scFv Viral Genomes In Vivo in Mice

To study anti-tau scFv antibody expression driven by CAG promoter in serum, CSF and/or CNS tissue of mice after intravenous delivery of AAV particles, viral genomes TAU_ITR139 (SEQ ID NO. 2189) and TAU_ITR152 (SEQ ID NO. 2202) were each packaged into VOY101 capsids. AAV particles were formulated in PBS and provided intravenously at a dose of 1.4×10¹³ vg/kg to 2 month-old female C57Bl/6 mice. 28 days after administration, mice were euthanized and CSF and/or tissue samples (hippocampus, cortex, thalamus, brain stem, spinal cord, olfactory bulb, liver, skeletal muscle) were collected for analysis. Study design is shown in Table 147.

TABLE 147 IPN002 IV study design SEQ End TAU_ITR ID Dose Dose of AAV Particle ID NO: μl (vg/kg) (vg) Route N study IPN002.scFv.CAG.HL.G4S-3 TAU_ITR139 2189 100 1.4 × 10¹³ 2.8 × 10¹¹ IV 6 Day 28 IPN002.scFv.CAG.LH.G4S-3 TAU_ITR152 2202 100 1.4 × 10¹³ 2.8 × 10¹¹ IV 6 Day 28 PBS — — 100 — — IV 4 Day 28

Vector genome was quantified for a subset of tissues, such as for brain, CSF, and/or peripheral tissue (e.g. liver) by droplet digital PCR and normalized per diploid cell (VG/DC). Antibody levels in the hippocampus, cortex, olfactory bulb, brainstem, spinal cord, liver, serum, and CSF were quantified using ePHF ELISA, as described above. Vector genome biodistribution quantification (VG/DC) is shown in Table 148.

TABLE 148 Vector genome quantification of VOY101.IPN002 constructs (AAV genomes/cell) TAU_ITR ID Olfactory Spinal (SEQ ID NO.) Hippocampus Cortex bulb Thalamus Brainstem Cord TAU_ITR139 33.49 24.86 34.14 47.33 59.68 38.72 (SEQ ID NO. 37.06 23.72 63.95 58.46 71.12 141.68 2189) 14.34 22.12 33.61 35.87 62.59 49.55 11.32 19.52 55.37 33.25 48.86 36.27 34 31.09 58.12 46.73 61.29 37.2 20.28 33 50.18 48.68 83.83 106.23 Average 25.08 25.72 49.23 45.05 64.56 68.28 TAU_ITR152 23.08 15.86 30.25 59.11 52.76 79.12 (SEQ ID NO. 2.78 3.38 10.85 6.84 9.77 12.14 2202) 17.73 24.05 14.82 28.73 38.81 28.67 32.01 25.15 43.66 73.5 79.95 116.56 17.37 21.38 28.08 33.4 51.58 42.41 3.46 8.82 7.33 11.04 16.31 10.79 Average 16.07 16.44 22.50 35.44 41.53 48.28 Vehicle (PBS) 0 0 0 0 0 0

Subsequent to intravenous delivery of IPN002-scFv VOY101 particles, biodistribution was observed in all CNS tissue noted in Table 148. Higher viral genome levels per diploid cell were observed with TAU_ITR139 (SEQ ID NO. 2189) with the IPN002.scFv.CAG.HL.G4S-3 (heavy-linker-light) configuration compared to TAU_ITR152 (SEQ ID NO. 2202) with the IPN002.scFv.CAG.LH.G4S-3 (light-linker-heavy) configuration.

ePHF ELISA was used to assess IPN002 antibody expression in tissues collected after intravenous injection of IPN002-scFv VOY101 particles. Samples of hippocampus, cortex, olfactory bulb, thalamus, brain stem and spinal cord were analyzed. Data are shown in Table 149 and Table 150 as ng/mg of protein and as normalized sFv/vg respectively.

TABLE 149 IPN002 expression in the CNS Hippocampus Cortex Olfactory bulb TAU_ITR ID ng/mg ng/mg ng/mg (SEQ ID NO.) protein scFv/Vg protein scFv/Vg protein scFv/Vg TAU_ITR139 352.56 10.53 590.74 23.76 1096.45 32.12 (SEQ ID NO. 422.05 11.39 578.91 24.41 1147.95 17.95 2189) 446.11 31.11 714.68 32.30 1011.01 30.08 400.01 35.34 580.23 29.72 660.91 11.94 448.99 13.20 629.62 20.25 1197.19 20.60 505.11 24.90 757.7 22.96 1126.88 22.46 Average 429.14 21.08 641.98 25.57 1040.07 22.53 TAU_ITR152 194.52 8.43 358.57 22.61 465.66 15.39 (SEQ ID NO. 24.19 8.69 33.18 9.81 44.32 4.08 2202) 74.93 4.23 138.41 5.76 225.37 15.20 233.75 7.30 454.64 18.08 599.41 13.73 292.5 16.84 464.74 21.74 772.8 27.52 57.63 16.66 95.61 10.84 190.22 25.93 Average 146.25 10.36 257.53 14.81 382.96 16.98 Vehicle (PBS) 0 0 0 0 0 0

TABLE 150 IPN002 expression in CNS and spinal cord TAU_ITR Thalamus Brainstem Spinal Cord ID (SEQ ID ng/mg scFv/V ng/mg ng/mg NO.) protein g protein scFv/Vg protein scFv/Vg TAU_ITR139 639.27 13.51 639.49 10.71 883.76 22.82 (SEQ ID NO. 808.44 13.83 1296.27 18.23 836.37 5.90 2189) 700.65 19.54 887.67 14.18 879.74 17.75 763.33 22.96 1043.87 21.37 870.09 23.99 786.91 16.84 675.48 11.02 986.58 26.52 913.07 18.76 1128.73 13.46 744.17 7.01 Average 768.61 17.57 945.25 14.83 866.79 17.33 TAU_ITR152 553.21 9.36 505.81 9.59 793.3 10.03 (SEQ ID NO. 54.94 8.04 78.31 8.01 99.97 8.23 2202) 223.88 7.79 214.98 5.54 458.31 15.99 522.09 7.10 656.5 8.21 900.14 7.72 702.19 21.02 645.19 12.51 486.98 11.48 161.88 14.66 266.84 16.35 202.79 18.79 Average 369.70 11.33 394.61 10.03 490.25 12.04 Vehicle (PBS) 0 0 0 0 0 0

High levels of IPN scFv were observed in the hippocampus, cortex and olfactory bulb of the mice dosed with IPN scFv vectors. Higher IPN scFv levels were observed with TAU_ITR139 (SEQ ID NO. 2189) with the IPN002.scFv.CAG.HL.G4S-3 viral genome configuration as compared to TAU_ITR152 (SEQ ID NO. 2202) with the IPN002.scFv.CAG.LH.G4S-3 viral genome configuration.

In serum and CSF samples collected on the terminal day, quantification of the IPN002 antibody expression demonstrated enhanced expression of IPN002 when delivered with VOY101 and driven by the CAG promoter. Consistent with other tissues, higher IPN scFv levels were observed with TAU_ITR139 (SEQ ID NO. 2189) with the IPN002.scFv.CAG.HL.G4S-3 configuration as compared to TAU_ITR152 (SEQ ID NO. 2202) with the IPN002.scFv.CAG.LH.G4S-3 configuration. These results are shown in Table 151.

TABLE 151 IPN002 expression in CSF and Serum TAU_ITR ID CSF Serum (SEQ ID NO.) ng/ml nM scFv ng/ml nM scFv TAU_ITR139 11926.1 477.04 54921 2196.84 (SEQ ID NO. 2189) 9711.8 388.47 119105 4764.20 9993.2 399.73 59057 2362.28 9846.95 393.88 28863.5 1154.54 11596.75 463.87 59741.5 2389.66 — — 124490.5 4979.62 Average 10614.96 424.60 74363.08 2974.52 TAU_ITR152 4702.4 188.10 9443.8 377.75 (SEQ ID NO. 2202) 1034.7  41.39 1083.95 43.36 9470.5 378.82 844.85 33.79 10020.6 400.82 3451.05 138.04 3368.35 134.73 5346.7 213.87 — — 1351.75 54.07 Average 5719.31 228.77 3587.017 143.48 Vehicle (PBS) 0 0  0 0

Liver samples collected on the terminal day, showed low IPN002 antibody expression and biodistribution of AAV genomes when delivered with VOY101. The results are shown in Table 152.

TABLE 152 Vector genome quantification and IPN002 expression in Liver Construct Genome/cell scFv/mg TAU_ITR139 7.50 222.83 (SEQ ID NO. 2189) 19.36 332.41 9.18 289.83 4.62 169.14 7.79 256.53 13.16 349.19 Average 10.27 269.99 TAU_ITR152 7.99 127.28 (SEQ ID NO. 2202) 0.36 12.55 0.22 9.41 2.87 42.79 3.13 90.54 0.59 19.05 Average 2.53 50.27 vehicle 0 0

Consistent with other tissues, the liver demonstrated higher IPN scFv levels with delivery of TAU_ITR139 (SEQ ID NO. 2189) with the IPN002.scFv.CAG.HL.G4S-3 configuration as compared to with delivery of TAU_ITR152 (SEQ ID NO. 2202) with the IPN002.scFv.CAG.LH.G4S-3 configuration.

Brain tissue samples were collected on the terminal day and fixed with 4% PFA for immunohistochemistry. Anti-IgG immunohistochemistry of brain tissue collected from mice injected with VOY101.IPN002-scFv AAV particles driven by CAG promoters and one of viral genome configurations (HL or LH) showed broad antibody expression across mouse CNS, but stronger staining in tissue of mice treated with HL configuration as compared to the LH configuration. Vehicle-treated control animals exhibited low background levels of staining. Expression of IPN002 antibody was observed in a non-cell type specific manner (neurons and astrocytes showed staining) across multiple brain regions, as may be expected when using ubiquitous promoters. Expression of IPN002 was also observed in the spinal cord.

Taken together, these data indicate that the ubiquitous CAG promoter may effectively drive IPN002 expression in CNS tissue of mice, with limited concomitant expression in peripheral tissues, such as the liver.

The IPN002 scFv expression levels in the hippocampus and cortex were compared to expression levels of full-length PT3 antibody, IPN002 Fab fragment and IPN002 F(ab′)2 fragment. Both the heavy chain-linker-light chain format as well as the light chain-linker-heavy chain format was considered for this analysis. Comparison of the expression levels showed that the scFv format resulted in higher expression in both the hippocampus and the cortex as compared to the other formats (e.g., full length antibody, Fab or F(ab′)2 fragment). PT3 expression levels of the full-length antibody in the heavy-linker-light chain format was higher than IPN002 expression from Fab or F(ab′)2 fragments.

Testing of PT3 scFv Viral Genomes In Vivo in Mice

To study anti-tau antibody PT3 scFv levels in serum, CSF and/or CNS tissue of mice after intravenous delivery of vector, viral genomes TAU_ITR162 (SEQ ID NO: 2212). TAU_ITR168 (SEQ ID NO: 2218); TAU_ITR165 (SEQ ID NO: 2215) were packaged into VOY101 capsids. AAV particles were formulated in PBS and provided intravenously at a dose of 1.4×10¹³ vg/kg into 2 month-old female C57Bl/6 mice. Twenty-eight days after administration, mice were sacrificed and CSF and/or tissue samples (hippocampus, cortex, thalamus, brain stem, spinal cord, olfactory bulb, liver, spleen) were collected for analysis. Study design is shown in Table 153.

TABLE 153 PT3 IV study design SEQ End TAU_ITR ID Dose Dose of AAV Particle ID NO: μL (vg/kg) (vg) Route N study ssAAV CAG PT3 VL G4S-3 TAU_ITR162 2212 100 1.4 × 10¹³ 2.8 × 10¹¹ IV 6 Day 28 VH HA rBGpA ssAAV SYN PTS VL G4S-3 TAU_ITR168 2218 100 1.4 × 10¹³ 2.8 × 10¹¹ IV 6 Day 28 VH HA rBGpA ssAAV GFAP PT3 VL G4S-3 TAU_ITP165 2215 100 1.4 × 10¹³ 2.8 × 10¹¹ IV 6 Day 28 VH HA rBGpA PBS — — 100 — — IV 4 Day 28

Vector genome distribution was quantified for a subset of tissues, such as for brain, CSF, and/or peripheral tissue (e.g. liver and spleen) by droplet digital PCR and normalized per diploid cell (VG/DC). Antibody levels in the hippocampus, cortex, olfactory bulb, brainstem, spinal cord, liver, serum, and CSF were quantified using ePHF ELISA, as described above. Vector genome biodistribution quantification (VG/DC) is shown in Table 154.

TABLE 154 Biodistribution of PT3-scFv viral genomes (AAV genomes/cell) Olfactory Spinal Construct Hippocampus Cortex bulb Thalamus Brainstem Cord TAU_ITR168 10.40 8.63 12.60 32.13 20.31 9.53 17.99 28.95 23.63 23.19 18.93 19.91 9.20 6.32 20.24 21.44 23.49 31.58 10.05 7.93 42.50 22.96 26.33 37.08 13.67 8.67 12.63 29.11 33.83 20.46 2.17 2.02 2.05 2.85 5.32 2.27 11.58 — 18.11 23.05 45.04 66.61 Average 10.72 10.42 18.82 22.10 24.75 26.78 TAU_ITR165 34.22 35.57 24.41 37.06 36.65 52.59 5.89 13.29 6.17 9.49 9.98 23.06 9.99 4.37 6.47 22.11 13.10 24.12 32.62 46.88 63.20 79.94 80.27 84.26 46.54 33.49 55.83 50.40 57.67 72.87 33.88 15.20 62.29 74.33 72.13 121.54 Average 27.19 24.80 36.40 45.56 44.97 63.07 TAU_ITR162 6.27 5.58 6.14 11.32 21.80 20.95 13.76 13.39 14.91 21.34 44.88 57.40 15.32 14.09 19.04 21.52 19.58 13.56 14.26 12.43 26.25 61.08 49.97 142.85 3.45 3.13 4.94 13.09 15.98 14.07 9.22 9.15 41.04 17.63 38.43 22.21 Average 10.38 9.63 18.72 24.33 31.77 45.17 Vehicle (PBS) 0 0 0 0 0 0

Subsequent to intravenous delivery of PT3-scFv VOY101 particles, biodistribution was observed in all tissues noted in Table 154. Higher viral genome levels per diploid cell were observed in hippocampus, cortex, olfactory bulb and thalamus with TAU_ITR165 with the ssAAV GFAP PT3 VL G4S-3 VH HA rBGpA configuration compared to the other two constructs.

ePHF ELISA was used to assess PT3 antibody expression in tissues collected after intravenous injection of VOY101 particles. Samples of hippocampus, cortex, olfactory bulb, thalamus, brain stem and spinal cord were analyzed. Data are shown in Table 155 and Table 156 as ng/mg of protein and as normalized scFv/vg.

TABLE 155 PT3 expression in the CNS Hippocampus Cortex Olfactory bulb ng/mg ng/mg ng/mg Construct protein scFv/Vg protein scFv/Vg protein scFv/Vg TAU_ITR168 0 0.00 3.63 0.42 3.69 0.29 0 0.00 3.04 0.11 3.75 0.16 0 0.00 2.50 0.40 — 0.00 0.98 0.10 2.74 0.35 2.48 0.06 0 0.00 3.66 0.42 8.17 0.65 0 0.00 2.68 1.33 — 0.00 — 0.00 2.64 — 1 0.06 Average 0.16 0.01 2.98 0.50 3.82 0.17 TAU_ITR165 4.03 0.12 25.74 0.72 47.4 1.94 0 0.00 2.95 0.22 1.14 0.18 0 0.00 2.50 0.57 4.69 0.72 2.26 0.07 16.53 0.35 39.03 0.62 8.12 0.17 22.94 0.69 119.67 2.14 0.99 0.03 5.36 0.35 28.34 0.45 Average 2.57 0.07 12.67 0.48 40.05 1.01 TAU_ITR162 1.8 0.29 7.67 1.37 22.36 3.64 5.35 0.39 15.81 1.18 53.01 3.56 17.84 1.16 46.60 3.31 83.61 4.39 18.15 1.27 67.42 5.42 146.79 5.59 0.97 0.28 5.64 1.80 16.3 3.30 8.47 0.92 53.74 5.87 119.46 2.91 Average 8.76 0.72 32.81 3.16 73.59 3.90 Vehicle (PBS) 0 0 0 0 0 0

TABLE 156 PT3 expression CNS and Spinal Cord Thalamus Brainstem Spinal cord ng/mg ng/mg ng/mg Construct protein scFv/Vg protein scFv/Vg protein scFv/Vg TAU_ITR168 43.31 1.35 10.96 0.54 45.01 4.72 6.8 0.29 84.36 4.46 101.41 5.09 5.41 0.00 9.93 0.00 20.4 0.00 8.68 0.38 40.66 1.54 46.43 1.25 9.39 0.32 70.55 2.09 151.37 7.40 0.18 0.06 1.18 0.22 0.78 0.34 0.47 0.02 4.53 0.10 10.41 0.16 Average 10.61 0.35 31.74 1.28 53.69 2.71 TAU_ITR165 4.74 0.13 25.21 0.69 47.53 0.90 0.46 0.05 — 0.00 0.75 0.03 0.31 0.01 — 0.00 1.16 0.05 2.02 0.03 53.61 0.67 41.26 0.49 7.38 0.15 30.78 0.53 42.07 0.58 1.66 0.02 17.33 0.24 12.04 0.10 Average 2.76 0.06 31.73 0.35 24.14 0.36 TAU_ITR162 8.5 0.75 29.97 1.37 63.13 3.01 9.7 0.45 108.83 2.43 60 1.05 52.26 2.43 119.14 6.08 91.33 6.73 34.43 0.56 86.61 1.73 102.92 0.72 11.48 0.88 25.31 1.58 58.59 4.16 26.63 1.51 108.26 2.82 61.24 2.76 — — 29.97 — — — Average 23.83 1.10 79.69 2.67 72.87 3.07 Vehicle (PBS) 0 0 0 0 0 0

PT3 scFv was observed in the hippocampus, cortex, olfactory bulb, thalamus, brainstem and spinal cord tissue of the mice dosed with PT3 scFv vectors. Higher PT3 scFv levels were observed with TAU_ITR62 with the ssAAV CAG PT3 VL G4S-3 VH HA rBGpA format as compared to the other two constructs.

In the serum and CSF samples collected on the terminal day, quantification of the PT3 antibody expression demonstrated enhanced expression of PT3 when delivered with VOY101. Consistent with other tissues, higher PT3 scFv levels were observed with TAU_ITR162 with the ssAAV CAG PT3 VL G4S-3 VH HA rBGpA as compared to the other two constructs. These results are shown in Table 157.

TABLE 157 PT3 expression in CSF and Serum CSF Serum Constructs ng/ml nM scFv ng/ml nM scFv TAU_ITR168 41.65 1.67 0 0.00 60.35 2.41 — 0.00 53.1 2.12 — 0.00 65.8 0.26 — 0.00 6.4 — — Average 45.46 1.62 0 0 TAU_ITR165 79.75 3.19 120.25 4.81 19.5 0.78 89.00 3.56 85.2 3.41 22.20 0.89 — — 81.75 3.27 Average 61.48 2.46 78.30 3.13 TAU_ITR162 66.3 2.65 78.15 3.13 151.8 6.07 63.80 2.55 166.1 6.64 111.15 4.45 97.55 3.90 202.10 8.08 227.35 9.09 127.90 5.12 — — 147.50 5.9 Average 141.82 5.67 121.80 4.87 Vehicle (PBS) 0 0   0 0

Liver and spleen samples collected on the terminal day, showed low PT3 antibody expression and biodistribution of AAV genomes when delivered with VOY101. The results are shown in Table 158.

TABLE 158 Vector genome quantification and PT3 expression in Liver & Spleen Liver Spleen Construct Genome/cell scFv ng/mg Genome/cell scFv/mg TAU_ITR168 1.05 2.95 1.42 1.55 1.75 2.51 7.70 1.62 0.09 1.90 2.35 1.6 0.77 1.90 4.07 2.11 1.06 1.64 22.68 1.73 0.02 2.37 0.52 2.65 0.05 2.24 18.72 — Average 0.68 2.22 8.21 1.88 TAU_ITR165 5.31 16.11 59.87 1.56 0.07 2.66 8.09 2.01 0.57 4.25 4.40 1.85 1.94 4.28 34.42 2.86 1.50 5.54 76.93 1.41 1.34 4.85 14.45 1.79 Average 1.79 6.28 33.03 1.91 TAU_ITR162 1.50 5.87 16.52 2.37 0.76 6.64 2.43 1.73 2.44 12.15 2.69 2.12 3.54 24.34 4.68 1.96 2.85 19.20 2.60 2.12 2.68 13.63 8.39 1.87 — — — 0.97 Average 2.29 13.64 6.22 1.88 Vehicle 0 2.29 0 1.48 — 1.78 — 1.6 — 2.22 — 1.53 — 1.77 — 1.19 Average 0 2.02 0 1.45

In comparison to CNS tissues, significantly lower AAV biodistribution was seen in peripheral tissues such as liver and spleen.

Brain tissue samples were collected on the terminal day and fixed with 4% PFA for immunohistochemistry. Anti-IgG immunohistochemistry of brain tissue collected from mice injected with VOY101.PT3 scFv AAV particles driven by CAG, GFAP or Syn promoters showed broad antibody expression across mouse CNS, but stronger and broader staining pattern was observed in the tissue of mice treated with VOY101.PT3 AAV particles driven by CAG promoter. Vehicle-treated control animals exhibited low background levels of staining. Expression of PT3 was also observed in the spinal cord.

Taken together, this study shows that PT3 is expressed in CNS tissues of all the experimental groups, with highest expression driven by the CAG promoter and cell-specific expression when driven by GFAP or synapsin promoters.

The PT3 antibody expression levels in the brain (hippocampus and cortex) and the CSF obtained with an scFv (light chain-linker-heavy chain) were compared to the full length PT3 antibody (light chain-linker-heavy chain). The PT3 levels in the cortex of mice dosed with full length antibody was similar to mice dosed with PT3 scFv. In the CSF, PT3 levels were higher in mice dosed with the full-length antibody as compared to the scFv. These observations were consistent across the different promoters tested i.e. CAG, SYN, and GFAP.

The PT3 antibody expression levels in the brain (hippocampus and cortex) and the CSF obtained with an scFv (light chain-linker-heavy chain) were compared to the full length PT3 antibody (heavy chain-linker-light chain). The PT3 expression levels in the brain and CSF of mice dosed with full length antibody was higher than the levels in mice dosed with PT3 scFv. In the CSF, PT3 levels were higher in mice dosed with the full-length antibody compared to the scFv. These observations were consistent across the different promoters tested i.e. CAG, SYN, and GFAP.

Example 20: VOY101.PT3 Promoter and Viral Genome Configuration Studies in Rodents Ubiquitous Promoters and T2A or F2 Linkers for PT3 Expression

To determine the effects of promoters and viral genome configurations on brain distribution, cellular tropism and expression levels of anti-tau antibody PT3 after intravenous delivery, single-stranded viral genomes described in Table 159 were packaged into VOY101 capsid. AAV particles were formulated in 0.001% F-68 and PBS and provided intravenously at a dose of 1.4×10¹³ vg/kg into 2 month-old female C57Bl/6 mice. Twenty-eight days after administration mice were sacrificed, perfused intracardially and CSF, serum, and/or tissue samples (hippocampus, cortex, thalamus, brain stem, spinal cord, olfactory bulb, liver, spleen, skeletal muscle) were collected for analysis. Study design is shown in Table 159 where N=6 for each AAV particle tested.

TABLE 159 PT3 IV study design SEQ End TAU_ITR ID Dose Dose of AAV Particle ID NO: μL (vg/kg) (vg) Route study Voy101.CAG.PT3.H.F.T2A.L TAU_ITR112 2162 100 1.4 × 10¹³ 2.8 × 10¹¹ IV Day 28 Voy101.CAG.PT3.LH.T2 TAU_ITR116 2166 100 1.4 × 10¹³ 2.8 × 10¹¹ IV Day 28 Voy101.CBA.PT3.H.F.T2A.L TAU_ITR111 2161 100 1.4 × 10¹³ 2.8 × 10¹¹ IV Day 28 Voy101.CBA.PT3.LH.T2A TAU_ITR115 2165 100 1.4 × 10¹³ 2.8 × 10¹¹ IV Day 28 Voy101.CAG.PT3.HL.F2 TAU_ITR104 2154 100 1.4 × 10¹³ 2.8 × 10¹¹ IV Day 28 Voy101.CAG.PT3.LH.F2 TAU_ITR108 2158 100 1.4 × 10¹³ 2.8 × 10¹¹ IV Day 28 Voy101.CBA.PT3.HL.F2A TAU_ITR103 2153 100 1.4 × 10¹³ 2.8 × 10¹¹ IV Day 28 Voy101.CBA.PT3.LH.F2A TAU_ITR107 2157 100 1.4 × 10¹³ 2.8 × 10¹¹ IV Day 28

Vector genome was quantified for a subset of tissues, such as for brain, CSF, and/or peripheral tissue (e.g. liver and spleen) by droplet digital PCR and normalized per diploid cell (VG/DC) using the endogenous mouse transferrin receptor gene (TFRC). Antibody levels in the hippocampus, cortex, olfactory bulb, brainstem, spinal cord, liver, serum, and CSF were quantified using ePHF ELISA with an anti-IgG as the detection antibody, as described above. The VG/DC values for the olfactory bulb (OB), cortex (CTX), hippocampus (HC), thalamus (THL), brainstem (BS), spinal cord (SC), spleen (SPL), liver (LIV) and muscle (MUS) are shown in Table 160. Average vector genome biodistribution quantification (VG/DC) in brain and spinal cord are shown in Table 161 and the peripheral tissues are shown in Table 162.

TABLE 160 Vector genome quantification of VOY101.PT3 constructs (AAV genomes/cell) TAU_ITR112 TAU_ITR116 TAU_ITR111 TAU_ITR115 Tissue (CAG.HFT2AL) (CAG.LHT2A) (CBA.HFT2AL) (CBA.LHT2A) OB 11.03 25.28 11.41 15.42 6.39 11.83 27.20 11.68 11.33 20.58 36.29 18.50 17.81 14.39 14.72 20.07 8.61 17.70 46.05 14.78 5.09 27.09 12.60 — 11.69 — 26.53 — 11.47 — 24.81 — 13.20 — — — CTX 17.56 29.89 12.05 22.36 14.16 13.84 39.46 14.14 21.45 18.43 35.00 25.34 19.58 18.94 37.14 26.28 11.55 18.12 42.07 21.75 8.47 13.02 31.06 — 14.59 — 2.6.68 — 12.84 — 28.73 — 14.91 — — — HC 13.70 19.93 7.14 15.12 27.76 17.47 20.19 25.90 10.69 19.13 19.35 25.69 20.17 11.60 18.99 23.79 10.38 14.22 21.24 15.54 14.94 17.37 16.59 — 10.32 — 18.77 — 13.46 — 20.62 — 8.39 — — — THL 25.10 38.02 14.29 43.81 23.11 37.28 50.31 38.69 15.01 57.03 42.69 62.34 26.77 43.54 52.98 64.33 40.46 30.53 42.49 29.84 19.23 24.86 20.92 — 19.53 — 22.68 — 26.68 — 26.50 — 22.20 — — — BS 24.15 68.89 19.56 60.15 26.46 45.99 60.70 34.52 74.69 47.46 64.97 87.17 26.54 43.39 66.11 43.45 9.53 50.89 45.11 44.2.1 17.27 46.93 33.47 — 42.60 — 39.50 — 22.49 — 41.19 — 22.67 — — — SC 16.17 36.43 8.40 33.2.1 15.00 23.51 33.91 25.42 41.81 46.00 30.21 85.83 23.25 28.88 33.69 59.40 11.11 25.02 30.41 21.07 11.43 32.08 28.01 — 15.34 — 16.43 — 21.09 — 35.39 — 12.89 — — — Spl 0.81 0.33 0.35 0.33 0.85 0.21 0.78 0.40 0.30 0.21 0.62 0.78 1.88 0.32 1.38 1.18 2.03 0.40 4.05 0.35 0.16 0.40 0.44 — 0.00 — 0.37 — 1.72 — 1.20 — 0.35 — — — Liv 2.10 4.33 10.04 5.96 3.78 1.76 7.99 1.92 3.12 4.54 6.03 2.20 3.23 2.28 42.83 4.63 2.57 3.17 27.63 2.57 0.72 3.19 8.98 — 2.89 — 14.96 — 3.26 — 19.22 — 3.00 — — — Mus 1.39 0.45 1.09 0.58 0.84 0.44 2.80 0.58 0.72 0.46 0.74 0.54 0.62 0.64 1.98 0.59 0.23 0.43 3.56 0.35 0.30 0.34 1.94 — 0.37 — 0.56 — 0.85 — 0.96 — 0.49 — — — TAU_ITR104 TAU_ITR108 TAU_ITR103 TAU_ITR107 Tissue (CAG.HLF2A) (CAG.LHF2A) (CBA.HLF2A) (CBA.LHF2A) PBS OB 18.95 10.14 13.81 14.12 0.00 8.90 10.56 12.24 17.31 0.00 9.60 23.73 15.78 13.45 0.00 7.80 17.21 8.70 8.02 0.02 25.44 7.90 11.72 17.90 0.00 10.44 6.16 7.72 12.12 0.00 — — — — 0.00 — — — — 0.00 — — — — 0.00 CTX 18.27 16.27 22.98 25.81 0.00 7.86 14.10 20.93 27.91 0.00 13.77 19.27 28.47 22.83 0.00 8.64 12.47 15.52 16.17 0.00 22.10 10.96 11.53 22.20 0.00 10.2.2 16.54 14.09 13.69 0.00 — — — — 0.01 — — — — 0.01 — — — — 0.00 HC 9.01 11.68 34.88 20.23 0.00 6.74 11.11 2.3.17 13.35 0.00 8.95 15.29 18.13 17.42 0.00 11.38 16.42 10.82 17.67 0.00 18.88 11.06 9.66 16.64 0.00 5.98 13.97 10.95 18.70 0.09 — — — — 0.02 — — — — 0.00 — — — — 0.00 THL 43.59 39.30 43.77 44.78 0.00 18.75 25.89 52.01 36.63 0.01 22.00 41.03 60.42 49.85 0.00 15.47 32.80 25.53 29.12 0.00 37.53 22.05 25.34 62.93 0.01 16.87 24.58 28.79 32.24 0.00 — — — — 0.02 — — — — 0.00 — — — — 0.01 BS 43.71 28.49 73.24 45.45 0.00 15.25 34.29 68.12 47.87 0.00 17.28 48.69 68.56 39.22 0.00 21.43 40.09 29.48 36.99 0.00 32.35 30.47 31.52 74.04 0.03 10.73 52.17 26.65 38.15 0.00 — — — — 0.00 — — — — 0.00 — — — — 0.00 SC 23.05 37.25 45.50 38.44 0.00 9.35 19.61 43.86 26.11 0.00 11.31 37.19 41.01 39.45 0.01 12.65 16.30 15.14 42.35 0.01 16.74 22.23 13.53 34.78 0.00 8.51 16.52 32.74 19.93 0.00 — — — — 0.03 — — — — 0.00 — — — — 0.00 Spl 0.43 0.32 0.46 0.44 0.00 0.14 0.34 0.38 0.28 0.00 0.28 0.63 0.79 0.43 0.00 0.82 0.16 0.29 0.26 0.00 0.15 0.22 0.29 0.79 0.00 0.23 0.16 0.25 0.35 0.00 — — — — 0.00 — — — — 0.00 — — — — 0.00 Liv 4.29 2.17 3.64 5.39 0.00 0.64 2.34 2.75 3.29 0.00 5.36 5.37 4.58 3.00 0.00 11.75 2.55 1.30 2.62 0.00 1.81 1.11 0.95 3.86 0.00 0.63 1.38 2.39 2.89 0.00 — — — — 0.00 — — — — 0.00 — — — — 0.00 Mus 0.62 0.25 0.66 1.54 0.00 0.25 0.19 0.45 0.70 0.00 0.22 0.53 0.67 0.58 0.00 0.14 0.48 0.48 0.23 0.00 0.50 0.18 0.34 0.47 0.00 0.19 0.17 0.28 0.33 0.00 — — — — 0.00 — — — — 0.01 — — — — 0.00

TABLE 161 Average vector genome quantification of VOY101.PT3 constructs (AAV genomes/cell) Olfactory Spinal Construct Hippocampus Cortex bulb Thalamus Brainstem Cord TAU_ITR112 14.42 15.01 10.73 24.23 29.60 18.68 (Voy101.CAG.PT3.H.F.T2A.L) TAU_ITR116 16.62 18.71 19.48 38.54 50.59 31.99 (Voy101.CAG.PT3.LH.T2) TAU_ITR111 17.86 31.52 24.95 34.11 46.33 27.06 (Voy101.CBA.PT3.H.F.T2A.L) TAU_ITR115 21.21 21.97 16.09 47.80 53.90 44.98 (Voy101.CBA.PT3.LH.T2A) TAU_ITR104 10.16 13.48 13.52 25.70 23.46 13.60 (Voy101.CAG.PT3.HL.F2) TAU_ITR108 13.26 14.93 12.62 30.94 39.03 24.85 (Voy101.CAG.PT3.LH.F2) TAU_ITR103 17.94 18.92 11.66 39.31 49.60 31.96 (Voy101.CBA.PT3.HL.F2A) TAU_ITR107 17.34 21.44 13.82 42.59 46.95 33.51 (Voy101.CBA.PT3.LH.F2A) Vehicle (PBS) 0.009 0.002 0.002 0.005 0.003 0.009

TABLE 162 Average vector genome quantification of VOY101.PT3 constructs (AAV genomes/cell) in peripheral tissues Skeletal Construct Spleen Liver Muscle TAU_ITR112 0.90 2.74 0.65 (Voy101.CAG.PT3.H.F.T2A.L) TAU_ITR116 0.31 3.21 0.46 (Voy101.CAG.PT3.LH.T2A) TAU_ITR111 1.15 17.21 1.71 (Voy101.CBA.PT3.H.F.T2A.L) TAU_ITR115 0.61 3.46 0.53 (Voy101.CBA.PT3.LH.T2A) TAU_ITR104 0.34 4.08 0.32 (Voy101.CAG.PT3.HL.F2A) TAU_ITR108 0.31 2.49 0.30 (Voy101.CAG.PT3.LH.F2A) TAU_ITR103 0.41 2.60 0.48 (Voy101.CBA.PT3.HL.F2A) TAU_ITR107 0.42 3.51 0.64 (Voy101.CBA.PT3.LH.F2A) Vehicle (PBS) 0.00 0.00 0.00

As shown in Table 160 Table 161, and Table 162, Voy101 delivery of 8 different formats of PT3 antibody encoding viral genomes comprising CAG or CBA promoters, and T2A or F2A cleavage sites showed biodistribution in all of the 6 tested CNS tissues. Biodistribution (e.g., vector genome levels) in the olfactory bulb, cortex, hippocampus, thalamus, brainstem, and spinal cord was similar for viral genomes comprising a T2A or F2A linker region. Biodistribution of viral genomes comprising a CBA promoter (e.g., CBA.HL and CBA.LH) trended towards slightly higher AAV genomes per cell within tested CNS tissues as compared to other viral genomes comprising CAG promoters. Biodistribution to peripheral tissues (liver, spleen, skeletal muscle) was low in comparison to that of CNS tissues, with the exception of TAU_ITR111 (Voy101.CBA.PT3.H.F.T2A.L).

Antibody levels in the hippocampus, cortex, olfactory bulb, brainstem, spinal cord, liver, serum, and CSF were quantified using ePHF ELISA, as described above. Samples of hippocampus (HC), cortex (MT), olfactory bulb (OB), thalamus (TH), brain stem (BS) and spinal cord (SC) were analyzed both as ng/mg of protein and as normalized scFv/vg. The results are shown in Table 163 and 164, respectively.

TABLE 163 PT3 expression in the CNS (ng PT3/mg protein) TAU_ITR112 TAU_ITR116 TAU_ITR111 TAU_ITR115 PBS (CAG.HFT2AL) (CAG.LHT2A) (CBA.HFT2AL) (CBA.LHT2A) HC 0 44.29 23.58 121.11 8.26 0 64.60 37.20 4.91 7.98 0 67.03 20.33 70.54 13.73 0 41.33 16.14 25.11 24.88 0 30.86 17.78 56.28 9.11 0 30.13 12.12 101.49 0 22.61 18.39 31.12 — 0 38.08 — 35.02 — 0 40.65 — — — Avg. 0 42.18 20.79 55.70 12.79 CTX 0 162.39 36.52 36.86 20.30 0 136.13 73.90 192.78 12.00 0 136.59 23.30 151.37 25.51 0 94.26 44.09 140.71 30.80 0 86.71 52.79 171.14 9.03 0 25.35 23.43 209.27 — 0 74.49 23.40 136.05 — 0 118.77 — 167.23 — 0 43.03 — — — Avg. 0 97.52 39.63 150.68 19.53 OB 0 105.24 38.26 76.91 28.74 0 96.03 60.60 155.09 24.62 0 99.53 29.97 155.12 43.93 0 103.88 51.72 149.64 39.86 0 82.33 49.53 185.73 27.87 0 51.29 38.77 176.50 — 0 41.51 53.10 188.16 — 0 136.42 — 185.63 — Avg. 0 89.53 45.99 159.10 33.00 TH 0 54.31 28.08 166.86 24.87 0 114.47 21.85 58.25 6.19 0 93.00 43.95 91.59 32.54 0 110.48 32.15 0.00 38.86 0 80.56 29.50 191.55 31.67 0 47.57 30.58 164.90 — 0 47.56 0.00 60.75 — 0 75.94 — 67.97 — 0 19.08 — — Avg. 0 71.44 26.59 100.23 26.83 BS 0 96.35 113.27 154.88 26.64 0 178.75 144.25 129.38 29.38 0 150.65 71.36 175.86 70.11 0 154.01 99.21 91.46 55.75 0 51.52 88.46 64.75 62.32 0 81.80 60.27 — 0 130.97 71.52 85.86 — 0 194.08 — 141.13 — 0 121.91 — — — Avg. 0 128.89 92.62 117.63 48.84 SC 0 36.66 21.72 21.54 17.70 0 60.48 42.48 58.99 6.43 0 47.93 21.91 79.29 35.65 0 53.22 24.96 66.36 33.10 0 27.91 18.86 79.45 13.42 0 34.85 14.87 70.11 — 0 47.83 5.48 84.88 — 0 34.29 34.29 18.70 — 0 40.89 40.89 — — Avg. 0 42.67 25.05 59.91 21.26 CSF 0 349.85 238.12 267.36 257.72 0 603.34 329.97 787.22 340.07 0 192.86 322.85 511.96 143.44 0 381.06 202.54 662.55 — 0 291.25 383.93 930.65 — 0 348.83 270.43 381.43 — 0 265.81 216.28 636.45 — 0 287.05 — — — 325.31 — — — Avg. 0 338.37 280.59 596.80 247.08 TAU_ITR104 TAU_ITR108 TAU_ITR103 TAU_ITR107 (CAG.HLF2A) (CAG.LHF2A) (CBA.HLF2A) (CBA.LHF2A) HC 1.26 13.99 16.56 11.46 7.30 3.27 7.16 6.42 0.15 13.37 4.88 18.50 2.98 5.75 1.87 6.23 3.28 39.23 1.11 8.87 1.25 5.77 1.35 6.61 — — — — — — — — — — — — Avg. 2.70 13.56 5.49 9.68 CTX 3.00 20.35 17.95 18.61 17.39 13.22 6.78 18.41 3.19 21.23 7.01 15.67 7.64 14.35 4.61 12.72 5.70 4.81 2.68 12.49 11.84 10.05 3.15 7.05 4.24 — — — — — — — — Avg. 7.57 14.00 7.03 14.16 OB 14.85 32.68 22.55 33.63 22.39 29.97 15.84 41.39 11.39 45.36 15.39 39.07 21.82 26.57 11.62 30.94 24.33 19.15 7.12 37.23 15.41 27.89 10.54 19.54 — — — — — — — — Avg. 18.36 30.27 13.85 33.63 TH 10.10 26.36 9.17 13.04 21.49 26.55 15.69 28.23 5.56 0.00 14.88 26.96 20.06 22.25 9.35 15.55 14.70 11.67 4.39 26.03 15.78 29.91 8.34 9.72 — — — — — — — — — — — — Avg. 14.62 19.46 10.30 19.92 BS 31.58 83.64 33.33 57.98 51.31 50.38 45.30 57.08 19.21 84.23 36.80 51.79 52.13 32.31 18.90 18.01 28.00 24.11 15.56 36.49 6.3.16 44.78 18.15 16.59 — — — — — — — — — — — — Avg. 40.90 53.24 28.01 39.66 SC 2.67 14.41 10.24 20.56 9.28 18.99 13.38 17.82 5.19 35.21 10.18 18.76 2.09 12.01 6.87 3.45 3.94 7.50 2.60 19.14 5.34 20.52 8.43 6.16 — — — — — — — — — — — — Avg. 4.75 18.11 8.62 14.32 CSF 0.00 96.29 62.69 23.36 15.41 26.58 90.95 76.84 44.17 42.68 29.47 64.18 93.11 143.84 20.43 48.76 — 0.00 41.20 61.42 — — — 20.98 — — — — — — — — — — — — Avg. 38.17 61.88 48.95 49.26

TABLE 164 Normalized PT3 expression in the CNS (PT3/vg) Olfactory Brain Spinal Hippocampus Cortex Bulb Thalamus stem cord TAU_ITR112 3.23 9.25 9.54 2.16 3.99 2.27 (CAG.HFT2AL) 2.33 9.61 15.03 4.95 6.76 4.03 6.27 6.37 8.78 6.20 2.02 1.15 2.05 4.81 5.83 4.13 5.80 2.29 2.97 7.51 9.56 1.99 5.41 2.51 2.02 2.99 10.08 2.47 4.74 3.05 2.19 5.11 3.55 2.44 3.07 3.12 2.83 9.25 11.90 2.85 8.63 1.63 — 2.89 — 0.86 5.38 3.17 Avg. 2.99 6.42 9.28 3.12 5.09 2.58 TAU_ITR104 0.14 0.95 0.78 0.53 0.72 0.12 (CAG.HLF2A) 1.08 0.41 2.52 2.42 3.37 0.99 0.02 0.55 1.19 0.58 1.11 0.46 0.26 0.66 2.80 2.57 2.43 0.16 0.17 0.54 0.96 0.58 0.87 0.24 0.21 0.41 1.48 1.51 5.89 0.63 Avg. 0.31 0.59 1.62 1.37 2.40 0.43 TAU_ITR116 1.87 2.47 1.51 1.11 1.64 0.60 (CAG.LHT2A) 1.16 1.68 5.12 1.85 3.14 1.81 0.84 2.39 1.46 2.14 1.50 0.48 1.53 2.79 3.59 2.23 2.29 0.86 0.85 1.29 2.80 1.67 1.74 0.75 1.06 1.80 1.43 1.13 1.28 0.46 Avg. 1.22 2.07 2.65 1.69 1.93 0.83 TAU_ITR108 1.21 1.25 3.25 2.62 2.93 0.40 (CAG.LHF2A) 0.29 0.90 2.84 2.52 1.52 0.98 0.88 1.10 1.91 0.00 1.76 0.93 0.36 1.15 1.54 1.29 0.79 0.70 3.25 0.43 2.44 1.48 0.80 0.31 0.42 0.59 4.78 5.13 0.90 1.25 Avg. 1.07 0.90 2.79 2.17 1.45 0.76 TAU_ITR111 16.96 3.06 6.74 11.68 7.92 2.56 (CBA.HFT2AL) 0.24 4.89 5.70 1.16 2.13 1.74 3.65 4.33 4.27 2.15 2.71 2.62 1.32 3.79 10.16 0.00 1.38 1.97 2.65 4.07 4.03 4.51 1.44 2.61 6.12 6.74 14.01 7.88 2.92 2.50 1.66 5.10 7.09 2.68 2.17 5.17 — 5.82 7.48 2.57 3.43 0.53 Avg. 4.66 4.72 7.44 4.08 3.01 2.46 TAU_ITR103 0.47 0.78 1.63 0.21 0.46 0.23 (CBA.HLF2A) 0.31 0.32 1.29 0.30 0.67 0.31 0.27 0.25 0.98 0.25 0.54 0.25 0.17 0.30 1.34 0.37 0.64 0.45 0.11 0.23 0.61 0.17 0.49 0.19 0.12 0.22 1.37 0.29 0.68 0.26 Avg. 0.24 0.35 1.20 0.26 0.58 0.28 TAU_ITR115 0.55 0.91 1.86 0.14 0.44 0.53 (CBA.LHT2A) 0.31 0.85 2.11 0.84 0.85 0.25 0.53 1.01 2.37 0.62 0.80 0.42 1.05 1.17 1.99 0.49 1.28 0.56 0.59 0.42 1.89 0.00 — 0.64 Avg. 0.60 0.87 2.04 0.42 0.85 0.48 TAU_ITR107 0.57 0.72 2.38 0.29 1.28 0.53 (CBA.LHF2A) 0.48 0.66 2.39 0.77 1.19 0.68 1.06 0.69 2.91 0.54 1.32 0.48 0.35 0.79 3.86 0.53 0.49 0.08 0.53 0.56 2.08 0.41 0.49 0.55 0.35 — 1.61 0.30 — 0.31 Avg. 0.56 0.68 2.54 0.48 0.95 0.44 Vehicle 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Avg. 0.00 0.00 0.00 0.00 0.00 0.00

Comparing the expression levels in the hippocampus to the expression in the cortex and olfactory bulb: PT3 was higher in the HL.T2A group (i.e. TAU_ITR111 (Voy101.CBA.PT3.H.F.T2A.L) and (TAU_ITR112 (Voy101.CAG.PT3.H.F.T2A.L)) than HL.F2A (TAU_ITR104 (Voy101.CAG.PT3.HL.F2) and (TAU_ITR103 (Voy101.CBA.PT3.HL.F2A)), regardless of whether a CAG or CBA promoter was used to drive expression. Based on the ePHF ELISA data for the cortex and the olfactory bulb, PT3 expression was significantly higher when driven by a CBA promoter rather than a CAG promoter regardless of the configuration of the viral genome (e.g., heavy-linker-light vs light-linker-heavy). No statistically significant differences were observed between PT3 expression driven by CBA or CAG promoter in the other tissues. In the hippocampus, thalamus and the brain stem, PT3 expression (ng/mg) was significantly higher (p value <0.005) when the rodents were transduced with TAU_ITR111 (Voy101.CBA.PT3.H.F.T2A.L) compared to rodents transduced with TAU_ITR115 (Voy101.CBA.PT3.LH.T2A). In the cortex, olfactory bulb and spinal cord, PT3 expression (ng/mg) was significantly higher when the rodents were transduced with TAU_ITR111 (Voy101.CBA.PT3.H.F.T2A.L) compared to rodents transduced with TAU_ITR115 (Voy101.CBA.PT3.LH.T2A) (p value <0.0005) and in rodents transduced with TAU_ITR112 (Voy101.CAG.PT3.H.F.T2A.L) compared to TAU_ITR116 (Voy101.CAG.PT3.LH.T2A) (p value <0.05 in the spinal cord; p value <0.005 in the cortex and olfactory bulb). In the cortex and olfactory bulb, PT3 expression (ng/mg) was significantly higher in mice treated with TAU_ITR111 (Voy101.CBA.PT3.H.F.T2A.L) compared to mice treated with TAU_ITR112 (Voy101.CAG.PT3.H.F.T2A.L) (p value <0.0005 in the olfactory bulb and p value <0.05 in the cortex).

Normalized PT3 expression was significantly increased in mice treated with TAU_ITR112 (Voy101.CAG.PT3.H.F.T2A.L) compared to mice treated with TAU_ITR116 (Voy101.CAG.PT3.LH.T2A) (p value <0.00005 in the cortex and olfactory bulb; p value <0.0005 in the brain stem and spinal cord). Similarly, normalized PT3 expression was significantly increased in mice treated with TAU_ITR111 (Voy101.CBA.PT3.H.F.T2A.L) when compared to mice treated with TAU_ITR115 (Voy101.CBA.PT3.LH.T2A) (p value <0.0005 in the cortex and spinal cord; p value <0.005 in the olfactory bulb; p value <0.05 in the thalamus). In the brain stem, normalized PT3 expression was significantly higher upon transduction of TAU_ITR112 (Voy101.CAG.PT3.H.F.T2A.L) compared to TAU_ITR111 (Voy101.CBA.PT3.H.F.T2A.L) (p value <0.05).

In CSF samples collected on the terminal day, quantification of the PT3 antibody expression demonstrated higher PT3 expression for constructs comprising T2A linkers (i.e. TAU_ITR112, TAU_ITR116, TAU_ITR111 and TAU_ITR115) than for constructs comprising F2A linkers (i.e. TAU_ITR104, TAU_ITR108, TAU_ITR103, TAU_ITR107). PT3 expression in the CSF was higher after delivery of a viral genome with CBA.HL format (i.e. TAU_ITR111) than after delivery of a viral genome with CBA.LH format (TAU_ITR115). For viral genomes with heavy-linker-light format, the CBA promoter (i.e. TAU_ITR111 and TAU_ITR103) drove greater PT3 expression than viral genomes comprising a CAG promoter (i.e. TAU_ITR112 and TAU_ITR104). No difference in expression was observed in mice transduced with VOY101 particles expressing constructs in the CAG.HL format (TAU_ITR112 and TAU_ITR104) and CAG.LH format (TAU_ITR116 and TAU_ITR108).

Immunohistochemistry was performed on brain tissue of mice treated with an IV bolus injection of ssVOY101.PT3 AAV particles comprising viral genomes encoding PT3, operably linked to CAG or CB6 promoters. PT3 (IgG) and astrocytic (S100β) markers were assessed for colocalization of PT3 with S100β positive cells. PT3 expression was detected in different brain regions of mice dosed with CAG.HL.PT3 vector, TAU_ITR112. Lower PT3 expression was observed in the brains of mice dosed with Voy101.CAG.LH.PT3 vector, TAU_ITR116. This same pattern was observed across format pairs, wherein the heavy-linker-light format yielded comparatively more staining than the light-linker-heavy format, regardless of the linker used (e.g., T2A or F2A). PT3 antibody expression also colocalized with S100β as well as cells that displayed neuronal morphology. Neuronal localization of PT3 antibody was also confirmed by immunofluorescence studies using neuronal marker NeuN which demonstrated colocalization with PT3 (IgG) in tissues obtained from mice injected with each of the constructs described in Table 159.

Comparing the PT3 expression obtained from T2A based constructs versus F2A constructs described in Table 159, showed that constructs with the HL format namely TAU_ITR112, TAU_ITR111, TAU_ITR104, and TAU_ITR103 showed higher PT3 expression compared to constructs with the LH format namely, TAU_ITR116, TAU_ITR115. TAU_ITR108 and TAU_ITR107, regardless of whether T2A or F2A was used. Generally, viral genomes comprising a T2A cleavage site, as opposed to an F2A cleavage site, showed higher levels of PT3 expression in the CNS and CSF as measured by ELISA.

Taken together, this study shows that PT3 antibody is expressed in CNS tissues of all the experimental groups, with no significant difference in PT3 levels per vector genome observed between constructs driven by the CAG promoter and the CBA promoter.

Comparing the PT3 expression levels observed in the brain (hippocampus, cortex and thalamus) obtained with PT3 constructs described in Table 159 with the IPN002 constructs described in Example 8, it was noted that in both instances, antibody expression levels were comparable and constructs with ubiquitous promoters (CAG or CBA) comprising a T2A cleavage site resulted in higher antibody (PT3 of IPN002) expression when compared to constructs with ubiquitous promoters (CAG or CBA) comprising an F2A cleavage site. IPN002 antibody expression levels were driven more robustly when a CAG promoter was used, whereas PT3 antibody expression was greater when driven by the CBA promoter. In general, IPN002 and PT3 constructs with ubiquitous promoters (CAG or CBA) that included a T2A and the antibody in the heavy chain-light chain format showed higher expression than T2A constructs with a light chain heavy format.

Cell-Type Specific Promoters for PT3 Expression

The effect of using cell-type specific promoters GFAP or synapsin (SYN) for driving expression of PT3 from four different viral genome configurations (HF.T2AL, LT2AH, HF.F2AL or LF2AH) was assessed based on measurement of brain distribution, cellular tropism and antibody expression level. Data from this study further enabled comparison of the effects of T2A and F2A cleavage sites on PT3 antibody expression, distribution and tropism.

Viral genomes TAU_ITR113 (SEQ ID NO. 2163), TAU_ITR117 (SEQ ID NO. 2167), TAU_ITR114 (SEQ ID NO. 2164). TAU_ITR118 (SEQ ID NO. 2168), TAU_ITR105 (SEQ ID NO. 2155), TAU_ITR109 (SEQ ID NO. 2159). TAU_ITR106 (SEQ ID NO. 2156), and TAU_ITR110 (SEQ ID NO. 2160), were packaged, single stranded, into VOY101 AAV particles and formulated in PBS and 0.001% F-68. Vehicle PBS with 0.001% F-68 was used as a control. An intravenous bolus at a dose of 1.4×10¹³ vg/kg was administered via tail vein to two-month old female C57Bl/6 mice. Twenty-eight days later, mice were sacrificed by intracardiac perfusion and tissue samples collected and processed for further analysis. The right half of the brain (including olfactory bulb) and lumbar spinal cord were post-fixed with 4% PFA for immunohistochemistry. The other half of the brain (dissected into hippocampus, cortex, thalamus, brainstem) and cervical and thoracic spinal cord tissues were processed for use in ELISA assays and vector genome quantification by droplet digital PCR normalized to diploid cell number (VG/DC) using the endogenous mouse transferrin receptor gene (TFRC). Peripheral tissues from spleen, liver and skeletal muscle were also collected. Serum samples were collected at two days prior to dosing, and weekly after dosing on days 7, 14, 21 and 28 (terminal day). CSF samples were collected on the terminal day (D28). The study design is shown in Table 165 below.

TABLE 165 PT3 IV study design SEQ End TAU_ITR ID Dose Dose of Test article ID NO: μl VG/kg Vg route N study GFAP.HF.T2A.L TAU_ITR113 2163 100 1.40E+13 2.80E+11 IV 9 D 28 GFAP.LH.T2 TAU_ITR117 2167 100 1.40E+13 2.80E+11 IV 6 D 28 SYN.HF.T2AL TAU_ITR114 2164 100 1.40E+13 2.80E+11 IV 9 D 28 SYN.LH.T2 TAU_ITR118 2168 100 1.40E+13 2.80E+11 IV 6 D 28 GFAP.HL.F2 TAU_ITR105 2155 100 1.40E+13 2.80E+11 IV 6 D 28 GFAP.LH.F2 TAU_ITR109 2159 100 1.40E+13 2.80E+11 IV 6 D 28 SYN.HL.F2 TAU_ITR106 2156 100 1.40E+13 2.80E+11 IV 6 D 28 SYN.LH.F2 TAU_ITR110 2160 100 1.40E+13 2.80E+11 IV 6 D 28 PBS — 100 n.a n.a IV 4 D 28

CNS, peripheral and serum samples were analyzed by ePHF ELISA. Brain, olfactory bulb and spinal cord tissues were assessed by immunohistochemistry (NeuN S100β, IgG), immunofluorescence and/or hematoxylin and eosin staining (H&E). Vector genome quantification using droplet digital PCR (ddPCR) was carried out for samples collected from cortex (CTX), hippocampus (HC), anterior olfactory bulb (OB), brain stem (BS), thoracic spinal cord (SC), thalamus (TH), liver, spleen, and skeletal muscle. Secondary readouts included daily cage side observations for 1 week after AAV particle administration and weekly body weight measurements. Vector genome quantifications (VG/DC) are shown in the Table 166 below.

TABLE 166 Vector genome quantification of ssVOY101.PT3 constructs TAU_ITR114 TAU_ITR118 TAU_ITR113 TAU_ITR117 PBS (SYN.HLT2A) (SYN.LHT2A) (GFAP.HLT2A) (GFAP.LHT2A) HC 0.01 19.25 20.91 13.56 34.61 0.01 51.14 62.89 10.55 46.43 0.06 18.75 25.33 18.24 17.57 0.01 11.39 63.78 20.10 26.96 0.00 7.97 33.66 49.67 36.65 0.00 14.99 42.15 14.78 42.71 0.00 18.79 — 26.07 — 0.00 12.87 — 41.19 — — 20.99 — 18.22 — Avg. 0.01 19.57 41.45 23.59 34.16 CTX 0.00 14.70 59.18 24.28 37.16 0.01 28.02 33.64 24.47 23.21 0.00 31.61 25.38 23.90 24.64 0.02 23.40 32.40 31.76 28.39 0.00 7.04 27.33 36.38 48.54 0.00 20.35 62.88 19.87 52.03 0.00 25.98 — 34.53 — 0.00 13.80 — 34.66 — 16.07 — 35.22 — Avg. 0.00 20.11 40.13 29.45 35.66 OB 0.00 6.03 48.78 15.19 57.56 0.00 20.33  8.38 3.10 29.66 0.00 18.69 29.48 17.12 15.53 0.00 7.16 29.55 36.82 28.82 0.00 5.49 23.79 22.73 33.59 0.00 14.86 12.97 15.25 51.84 0.00 27.58 — 30.13 — 0.02 16.35 — 42.10 — 21.47 — 18.78 — Avg. 0.00 15.33 25.49 22.36 36.17 TH 0.01 20.40 229.00  32.09 41.58 0.00 51.20 36.82 23.25 32.98 0.06 40.21 207.63  30.81 55.41 0.00 26.05 232.78  38.21 105.17  0.00 7.82 184.74  43.81 41.36 0.01 28.39 42.62 25.09 69.23 0.00 27.67 — 42.05 — 0.00 18.32 — 41.98 — 24.01 — 44.53 — Avg. 0.01 27.12 155.60  35.76 57.62 BS 0.00 22.20 31.10 35.32 109.90  0.06 46.25 102.52  26.03 38.26 0.01 47.05 165.28  41.68 80.22 0.02 26.71 50.57 53.04 99.61 0.00 9.66 27.83 51.72 49.34 0.00 34.54 50.73 24.94 132.43  0.00 57.33 — 61.72 — 0.00 34.05 — 51.76 — 52.59 — 53.14 — Avg. 0.01 36.71 71.34 44.37 84.96 SC 0.02 12.63 55.71 20.02 41.26 0.00 23.52 30.66 13.16 45.67 0.01 23.18 234.44  22.87 66.02 0.01 21.32 69.92 25.01 71.70 0.00 4.30 29.48 93.99 45.59 0.00 28.88 32.72 19.45 71.37 0.01 25.01 — 29.22 — 0.01 14.15 — 28.30 — 22.80 — 69.61 — Avg. 0.01 19.53 75.49 35.74 56.93 TAU_ITR106 TAU_ITR110 TAU_ITR105 TAU_ITR109 (SYN.HLF2A) (SYN.LHF2A) (GFAP.HLF2A) (GFAP.LHF2A) HC 23.69 27.95 27.21 22.27 27.04  0.26 25.35 39.38 35.50 17.85 25.90 10.75 128.16  25.89 28.65 48.17 28.96  4.91 29.76 21.96 29.09 44.57 18.38 25.36 — — — — — — — — — — — — Avg. 45.41 20.24 25.88 27.98 CTX 17.10 29.05 34.18 26.99 43.23  0.36 21.34 49.96 28.30 22.09 26.54 19.11 71.28 38.38 15.73 44.82 25.45  5.64 42.75 36.38 29.04 24.62 31.08 62.02 — — — — — — — — — — — — Avg. 35.73 20.02 28.60 39.88 OB 20.57 49.11 22.53 12.62 38.79  0.34 27.02 20.34 17.77 39.36 14.16 32.17 18.55 28.85  9.81 37.46 39.88  7.26 38.96 72.44 19.44 22.87 21.94 42.74 — — — — — — — — — — — — Avg. 25.84 24.63 22.40 36.29 TH 58.55 39.01 29.31 51.71 64.07  0.44 38.35 35.27 60.02 50.02 20.17 20.43 55.58 33.76 21.29 82.81 36.88 10.18 59.58 33.71 40.03 54.62 24.52 63.61 — — — — — — — — — — — — Avg. 52.52 31.34 32.20 47.92 BS 24.77 32.99 67.09 49.48 56.04  0.39 24.33 48.96 90.96 60.80 111.66  29.63 173.87  58.40 15.96 66.14 73.88 14.50 55.40 69.48 145.74  77.95 48.63 84.84 — — — — — — — — — — — — Avg. 94.21 40.84 53.84 58.09 SC 75.62 28.92 37.12 122.50  108.09   0.18 42.17 33.47 66.58 24.03 81.91 20.62 53.83 43.88 10.57 24.36  0.00 20.65 40.76 90.37 48.26 25.74 23.29 40.89 — — — — — — — — — — — — Avg. 58.73 23.90 39.30 55.37

Across the six CNS tissues analyzed, TAU_ITR118 (SYN.LH. T2A) showed higher AAV biodistribution in hippocampus, cortex, olfactory bulb, thalamus and spinal cord. In the brain stem, TAU_ITR106 (SYN.HL. F2A) showed the highest AAV biodistribution. The remaining AAV viral genomes tested demonstrated fairly similar AAV biodistribution.

Comparing the AAV biodistribution of TAU_ITR112 (CAG.PT3.HFT2AL; SEQ ID NO: 2162) described in Table 160 with TAU_ITR113 (GFAP.PT3.HLT2A; SEQ ID NO: 2163) or TAU_ITR114 (SYN.PT3.HLT2A; SEQ ID NO: 2164), GFAP.PT3.HLT2A resulted in significantly higher expression in the cortex compared to CAG.PT3.HFT2AL (p value <0.0005, one-way ANOVA-Tukey's multiple comparison test) or SYN.PT3.HLT2A (p value <0.005). In the thalamus, AAV biodistribution in mice treated with TAU_ITR113 was significantly higher than the mice treated with TAU_ITR112 (p value <0.05). The vector genome quantification in peripheral tissues is provided in Table 167.

TABLE 167 Vector genome quantification of ssVOY101.PT3 constructs in peripheral tissues TAU_ITR114 TAU_ITR118 TAU_ITR113 TAU_ITR117 PBS (SYN.HLT2A) (SYN.LHT2A) (GFAP.HLT2A) (GFAP.LHT2A) Liver 0.00 2.00 4.34 3.86 6.50 0.00 4.03 3.29 1.73 6.41 0.00 3.70 9.50 4.76 7.38 0.00 5.31 4.78 2.64 5.81 0.00 1.03 13.80  4.43 1.22 0.00 2.06 3.74 8.77 8.33 0.00 3.85 — 6.95 — 0 00 2.72 — 6.06 — 3.25 — 1.56 — Avg. 0.00 3.11 6.58 4.53 5.94 Spleen 0.00 0.92 0.41 10.97 7.05 0.00 0.80 4.07 0.22 1.06 0.00 15.69 0.59 14.33 0.81 0.00 0.57 19.40  0.55 0.67 0 00 0.19 5.48 0.59 0.78 0.00 0.15 0.77 37.74 1.03 0.00 5.84 — 8.54 — 0.00 1.48 — 0.57 — 0.27 — 1.94 — Avg. 0.00 2.88 5.12 8.38 1.90 Skeletal 0.00 0.68 1.78 1.10 0.95 Muscle 0.00 1.45 5.56 0.39 0.85 0.00 1.07 0.64 0.93 0.67 0.00 0.76 0.25 1.53 1.58 0.00 0.39 0.29 2.74 0.81 0.00 0.55 1.10 0.70 0.60 0.00 2.21 — 1.05 — 0.00 0.70 — 1.17 — 0.64 — 0.90 — Avg. 0.00 0.94 1.60 1.17 0.91 TAU_ITR106 TAU_ITR110 TAU_ITR105 TAU_ITR109 (SYN.HLF2A) (SYN.LHF2A) (GFAP.HLF2A) (GFAP.LHF2A) Liver 1.91 3.38 5.32 1.51 6.81 0.00 3.90 4.08 6.60 7.60 8.66 4.04 12.00  4 17 2.71 7.62 11.65  1.08 4.69 8.29 18.58  4.09 2.50 3.97 — — — — — — — — — — — — Avg. 9.59 3.39 4.63 4.92 Spleen 1.30 0.43 32.61  0.56 16.82  0.51 0.76 1.55 10.11  4.72 1.21 0.09 3.36 16.62  9.64 3.10 5.70 1.20 0.47 0.82 12.35  2.70 1.12 4.43 — — — — — — — — — — — — Avg. 8.27 4.36 7.63 1.76 Skeletal 1.12 0.36 1.33 0.56 Muscle 2.03 0.44 1.24 0.55 0.61 0.52 0.77 0.79 0.55 0.47 0.34 0.46 0.76 0.15 0.63 0.95 0.43 0.28 0.39 1.14 — — — — — — — — — — — — Avg. 0.92 0.37 0.78 0.74

As shown in Table 167, AAV biodistribution of the various viral genomes tested showed that the biodistribution in the peripheral tissues was much lower than the biodistribution observed in the CNS.

Samples of hippocampus, cortex, olfactory bulb, thalamus, brainstem, spinal cord, liver, spleen, skeletal muscle and serum were subjected to analysis by ePHF ELISA to determine PT3 expression from each of tbc cell-type specific PT3 viral genomes tested. Control studies were performed to confirm the standard curve and determine that the matrix effect is not observed in this ELISA assay. PT3 antibody expression was then normalized to the viral genome biodistribution (PT3/VG). Data are shown in Table 168 below as ng/mg protein (or ng/mL for serum samples) and Table 169 as PT3/vg (shortened to ab/vg).

TABLE 168 PT3 expression (ng PT3/mg protein) TAU_ITR114 TAU_ITR118 TAU_ITRU3 TAU_ITR117 PBS (SYN.HLT2A) (SYN.LHT2A) (GFAP.HLT2A) (GFAP.LHT2A) HC 0 10.93 1.87 6.45 3.32 0 27.86 3.05 14.35 5.18 0 17.91 2.54 28.98 0.78 0 8.17 4.78 9.06 1.55 0 −0.63 2.94 12.14 1.48 0 17.55 0 16.30 3.55 0 8.56 — 18.60 — 0 19.96 — — — — 17.32 — — — Avg. 0 14.18 2.53 15.12 2.64 CTX 0 12.15 6.46 49.00 10.83 0 25.42 6.02 15.75 14.66 0 23.33 8.47 41.61 5.17 0 16.00 13.86 50.37 7.86 0 2.24 8.21 69.70 12.22 0 46.93 9.19 41.81 19.89 0 56.18 — 68.12 — 0 29.68 — 42.17 — Avg. 0 26.49 8.70 47.32 11.77 OB 0 19.47 14.15 59.57 30.68 0 58.45 19.67 43.29 53.70 0 115.91 15.69 153.88 56.29 0 79.90 12.41 151.17 82.15 0 4.62 19.47 110.06 97.04 0 67.05 24.42 209.14 133.00 0 72.37 — 187.76 — 0 54.52 — 233.63 — — 90.94 — 135.86 — Avg. 0 62.58 17.64 142.71 75.48 TH 0 28.37 25.95 28.43 4.86 0 89.14 20.82 6.14 6.34 0 74.84 32.33 29.82 4.03 0 84.59 25.53 30.61 2.13 0 9.01 23.38 11.69 9.79 0 39 4.75 16.15 14.6 0 101.52 — 24.96 — 0 21.89 — 16.96 — — 75.46 — — — Avg. 0 58.20 22.13 20.60 6.96 BS 0 44.59 16.11 56.24 10.8 0 79.98 18.31 33.04 13.05 0 72.07 25.29 134.39 13.87 0 42.39 17.80 57.02 9.72 0 13.27 15.10 75.84 10.27 0 58.28 20.09 37.94 15.51 0 85.51 — 60.70 — 0 62.06 — 46.41 — — 70.87 — — — Avg. 0 58.78 18.78 62.70 12.20 SC 0 46.55 25.67 53.03 11.27 0 86.71 44.13 34.72 15.04 0 96.74 23.73 29.93 7.25 0 73.22 32.70 45.11 8.27 0 9.62 22.02 32.53 9.53 0 59.44 13.28 28.94 16.83 0 103.70 — 90.90 — 0 79.46 — 44.64 — — 59.52 — 123.22 — Avg. 0 68.33 26.92 53.67 11.37 Liver −0.09 0.65 0.34 8.01 7.51 −0.13 0.80 0.30 5.09 26.68 −0.08 1.00 0.48 13.78 42.32 −0.09 0.13 0.05 7.78 39.09 0.00 1.05 −0.27 11.18 22.21 −0.03 1.00 0.15 17.62 — −0.07 0.89 — 13.36 — −0.08 0.35 — 10.70 — Avg. 0 0.73 0.18 10.94 27.56 Spleen 1.64 0.66 0.33 18.16 17.39 −1.28 −0.82 0.14 −4.00 20.10 −1.27 0.85 2.00 5.99 55.44 0.57 2.62 −0.10 5.21 36.70 −1.33 3.11 1.43 16.41 0.53 −1.52 0.65 0.19 6.49 74.95 −1.45 1.01 — 11.45 — −2.38 0.75 — 10.07 — Avg. −1 1.10 0.67 8.72 34.19 Muscle 0 0.97 0.74 1.55 2.46 0 1.79 0.35 3.30 2.47 0 2.58 0.51 11.39 2.38 0 9.07 0.64 21.62 2.60 0 1.73 1.88 30.43 0.62 0 5.48 0.40 0.00 6.48 0 16.19 — 0.00 — 0 10.84 — 18.93 — — 0.72 — 5.03 — Avg. 0 5.49 0.75 10.25 2.83 TAU_ITR106 TAU_ITR110 TAU_ITR105 TAU_ITR109 (SYN.HLF2A) (SYN.LHF2A) (GFAP.HLF2A) (GFAP.LHF2A) HC 9.11 1.83 0.54 0.24 14.16 −1.49 0.08 1.49 5.39 1.57 0.13 −0.59 10.2 2.03 −0.54 0.33 5.8 −0.73 0.16 0.41 7.04 2.16 −0.39 0.29 — — — — — — — — — — — — Avg. 8.62 0.90 0.00 0.36 CTX 6.82 5.77 2.31 3.94 14.79 0.00 3.14 7.28 9.02 1.97 2.97 1.19 9.81 4.11 0.46 4.05 4.04 0.23 3.05 6.82 4.60 5.31 1.24 5.70 — — — — — — — — Avg. 8.18 2.90 2.20 4.83 OB 19.49 4.15 23.62 11.92 20.44 0.00 2.21 29.34 17.12 6.83 9.99 14.29 30.58 12.02 4.72 21.99 12.75 1.29 14.17 41.27 25.95 13.92 13.52 34.12 — — — — — — — — — — — — Avg. 21.06 6.37 11.37 25.49 TH 10.41 16.13 3.43 1.19 31.57 0 3.64 3.41 29.82 1.05 1.62 1.3 27.54 14.76 0 3.73 15.52 1.69 0.29 5.25 29.58 16.56 0.41 3.86 — — — — — — — — — — — — Avg. 24.07 8.37 1.57 3.12 BS 24.52 16.05 0.06 1.43 41.63 0.00 1.14 7.76 21.17 8.87 3.40 3.60 41.11 24.03 0.29 2.18 32.40 8.36 4.23 9.39 44.11 22.37 3.17 14.72 — — — — — — — — — — — — Avg. 34.16 13.28 2.05 6.51 SC 33.43 31.66 10.63 6.52 73.11 0.00 5.11 11.46 47.52 14.82 7.47 3.05 68.34 11.73 1.29 6.97 52.26 5.95 5.61 9.52 42.91 28.6 4.41 10.27 — — — — — — — — — — — — Avg. 52.93 15.46 5.75 7.97 Liver 0.52 0.10 4.30 8.14 0.30 −0.04 3.60 14.99 −0.24 −0.03 30.70 22.07 −0.03 0.11 10.27 22.68 0.15 0.02 6.17 31.91 0.37 0.13 0.97 17.71 — — — — — — — — Avg. 0.18 0.05 9.33 19.58 Spleen 0.10 −0.34 4.20 2.24 0.48 −0.57 3.74 4.27 −1.23 −0.21 5.56 29.90 0.02 −0.22 2.70 29.66 0.48 −0.72 3.83 9.22 0.87 −0.49 2.71 5.43 — — — — — — — — Avg. 0.12 −0.42 3.79 13.45 Muscle 0.14 0.00 0.52 0.39 0.40 0.00 1.0.3 2.9.3 0.37 0.18 1.58 6.70 0.33 0.21 0.73 2.41 0.91 0.02 0.76 8.27 0.46 0.02 0.99 18.48 — — — — — — — — — — — — Avg. 0.44 0.07 0.93 6.53

TABLE 169 PTS expression (PT3/vg) TAU_ITR114 TAU_ITR118 TAU_ITR113 TAU_ITR117 PBS (SYN.HLT2A) (SYN.LHT2A) (GFAP.HLT2A) (GFAP.LHT2A) HC 0 0.57 0.09 0.61 0.10 0 0.54 0.05 0.79 0.11 0 0.96 0.10 1.44 0.04 0 0.72 0.07 0.18 0.06 0 0.00 0.09 0.82 0.04 0 1.17 0.00 0.63 0.08 0 0.46 — 0.45 — 0 1.55 — — — Avg. 0 0.75 0.07 0.70 0.07 CTX 0 0.83 0.11 2.02 0.29 0 0.91 0.18 0.64 0.63 0 0.74 0.33 1.74 0.21 0 0.68 0.43 1.59 0.28 0 0.32 0.30 1.92 0.25 0 2.31 0.15 2.10 0.38 0 2.16 — 1.97 — 0 — — 1.22 — Avg. 0 1.13 0.25 1.65 0.34 OB 0 3.23 0.29 3.92 0.53 0 2.88 2.35 13.95  1.81 0 6.20 0.53 8.99 3.62 0 11.16 0.42 4.11 2.85 0 0.84 0.82 4.84 2.89 0 4.51 1.88 13.72  2.57 0 2.62 — 6.23 — 0 3.34 — 5.55 — 0 4.24 — 7.23 — Avg. 0 4.34 1.05 7.61 2.38 TH 0 1.39 0.11 0.89 0.12 0 1.74 0.57 0.26 0.19 0 1.86 0.16 0.00 0.07 0 3.25 0.11 0.78 0.02 0 1.15 0.13 0.70 0.24 0 1.37 0.11 0.47 0.21 0 3.67 — 0.38 — 0 1.20 — 0.59 — 0 3.14 — 0.38 — Avg. 0 2.09 0.20 0.49 0.14 BS 0 2.01 0.52 1.59 0.10 0 1.73 0.18 1.27 0.34 0 1.53 0.15 3.22 0.17 0 1.59 0.35 1.08 0.10 0 1.37 0.54 1.47 0.21 0 1.69 0.40 1.52 0.12 0 1.49 — 0.98 — 0 1.82 — 0.90 — 0 1.35 — — Avg. 0 1.62 0.36 1.50 0.17 SC 0 3.69 0.46 2.65 0.27 0 3.69 1.44 2.64 0.33 0 4.17 0.10 1.31 0.11 0 3.43 0.47 1.80 0.12 0 2.24 0.75 0.35 0.21 0 2.06 0.41 1.49 0.24 0 4.15 — 3.11 — 0 5.62 — 1.58 — 0 2.61 — 1.77 — Avg. 0 3.52 0.60 1.85 0.21 TAU_ITR106 TAU_ITR110 TAU_ITR105 TAU_ITR109 (SYN.HLF2A) (SYN.LHF2A) (GFAP.HLF2A) (GFAP.LHF2A) HC 0.38 0.07 0.02 0.01 0.52 0.00 0.00 0.04 0.15 0.09 0.00 0.00 0.08 0.08 0.00 0.01 0.20 0.00 0.01 0.02 0.24 0.05 0.00 0.01 — — — — — — — — Avg. 0.26 0.05 0.01 0.01 CTX 0.40 0.20 0.07 0.15 0.34 0.00 0.15 0.15 0.32 0.09 0.11 0.06 0.14 0.11 0.03 0.09 0.16 0.04 0.07 0.19 0.16 0.22 0.04 0.09 — — — — — — — — Avg. 0.25 0.11 0.08 0.12 OB 0.95 0.08 1.05 0.94 0.53 0.00 0.08 1.44 0.96 0.17 0.71 0.44 1.65 0.42 0.48 0.48 0.32 0.18 0.36 0.57 1.33 0.61 0.62 0.44 — — — — — — — — — — — — Avg. 0.96 0.24 0.55 0.72 TH 0.18 0.41 0.12 0.02 0.49 0.00 0.09 0.10 0.50 0.02 0.08 0.06 0.50 0.44 0.00 0.05 0.42 0.17 0.00 0.16 0.74 0.30 0.02 0.06 — — — — — — — — — — — — Avg. 0.47 0.22 0.05 0.07 BS 0.99 0.49 0.00 0.03 0.74 0.00 0.05 0.16 0.23 0.15 0.03 0.12 0.24 0.41 0.02 0.03 0.44 0.58 0.08 0.14 0.30 0.29 0.07 0.17 — — — — — — — — — — — — Avg. 0.49 0.32 0.04 0.11 SC 0.44 1.09 0.29 0.05 0.68 0.00 0.12 0.34 0.71 0.62 0.09 0.15 1.27 0.27 0.12 0.29 0.00 0.29 0.14 0.11 0.89 1.11 0.19 0.25 — — — — — — — — — — — Avg. 0.67 0.56 0.16 0.20

PT3 expression was evident in all CNS tissue tested and limited expression was detected in the peripheral tissues of mice treated with each of the viral genomes. Higher PT3 expression (ng/mg or PT3/vg) was observed when mice were administered HL.T2A viral genomes (i.e. TAU_ITR114 (SYN.HL.T2A); TAU_ITR113 (GFAP.HL.T2A) regardless of the promoter used when compared to PT3 expression obtained with HL.F2A configuration (i.e. TAU_ITR106 (SYN.HL. F2A); TAU_ITR105 (GFAP.HL.F2A).

Comparing the PT3 expression in mice treated with TAU_ITR112 (Voy101.CAG.PT3.H.F.T2A.L) described in Table 163 with TAU_ITR113 (GFAP.HL.T2A) or TAU_ITR114 (SYN.HL.T2A), CAG.PT3.H.F.T2A.L resulted in significantly higher expression in the cortex, hippocampus and thalamus compared to GFAP.HL.T2A (p value <0.005 (cortex) and <0.0005 (hippocampus and thalamus). Expression of PT3 in cortex and hippocampus of mice treated with CAG.PT3.H.F.T2A.L was also higher in comparison to PT3 expression in mice treated with SYN.HL.T2A (p value <0.0005). In the thalamus, SYN.HL.T2A resulted in higher PT3 expression compared to GFAP.HL.T2A (p value <0.005).

PT3 expression in the CSF and serum were also measured (Table 170).

TABLE I70 PTS expression (PT3/vg) in serum and CSF TAU_ITR114 TAU_ITR118 TAU_ITR113 TAU_ITR117 PBS (SYN.HLT2A) (SYN.LHT2A) (GFAP.HLT2A) (GFAP.LHT2A) Serum 0 1422.62 3588.88 27805.72 244053.65 0 387.99 4257.08 126354.36 158211.62 0 32720.22 4372.04 116784.02 280417.29 0 10216.99 3078.75 164247.74 349567.81 0 6078.46 3387.70 163730.42 175380.03 0 19270.01 3064.38 249475.50 569538.00 0 — — 272754.71 — 0 — — 92470.18 — Avg. 0 11682.71 3624.80 151702.83 296194.73 CSF 0 227.49 0 445.07 116.53 0 315.66 158.17 109.68 120.10 0 269.25 123.37 182.48 0.00 0 383.49 216.18 223.62 135.56 0 87.67 185.84 313.16 196.55 0 416.69 497.31 170.67 0 336.56 — 249.55 — 0 379.55 — 315.74 — 349.95 — — — Avg. 0 307.37 136.71 292.08 123.23 TAU_ITR106 TAU_ITR110 TAU_ITR105 TAU_ITR109 (SYN.HLF2A) (SYN.LHF2A) (GFAP.HLF2A) (GFAP.LHF2A) Serum 12652.76 4884.64 34214.00 27938.64 15906.61 308.06 20636.41 63613.08 11261.80 4041.58 62015.72 56539.05 15037.26 4808.57 39918.86 86166.33 6120.22 1404.67 57718.05 89931.54 6741.18 6895.28 24363.59 69774.34 — — — — — — — — Avg. 11286.64 3723.80 39811.11 65660.50 CSF 109.39 31.44 30.55 25.20 215.29 0 19.54 63.57 163.53 0 26.98 215.29 203.69 64.76 25.20 59.71 237.30 11.81 54.05 201.31 37.99 — — — — — — — — — — — — Avg. 188.42 24.33 25.57 83.56

In T2A group, the serum of mice treated with viral genome configuration TAU_ITR117 (GFAP.LH. T2A) demonstrated a significantly higher PT3 expression compared to mice treated with TAU_ITR114 (SYN.HL.T2A); TAU_ITR118 (SYN.LH. T2A); or TAU_ITR113 (GFAP.HL.T2A) (p value <0.0005; 2 way ANOVA). PT3 expression in the serum of mice treated with TAU_ITR114 (SYN.HL.T2A) was also significantly higher than the expression in the serum of mice treated with TAU_ITR118 (SYN.LH. T2A); and significantly lower than the PT3 expression after administration of TAU_ITR113 (GFAP.HL.T2A) (p value <0.0005). No significant difference in PT3 expression was observed in mice treated with any of the F2A based genome configurations. The CSF of mice treated with TAU_ITR114 (SYN.HL.T2A) showed significantly higher PT3 expression compared to mice treated with TAU_ITR117 (GFAP.LH. T2A) (p value <0.0005) or TAU_ITR118 (SYN.LH. T2A) (p value <0.005). Similarly, PT3 expression in the CSF of mice treated with TAU_ITR113 (GFAP.HL.T2A) was higher than the expression in mice treated with TAU_ITR117 (GFAP.LH. T2A) or TAU_ITR118 (SYN.LH. T2A) (p value <0.005). In the F2A cohort, PT3 expression in the CSF was significantly greater in mice treated with TAU_ITR114 (SYN.HL.T2A) compared to mice treated with TAU_ITR118 (SYN.LH. T2A) (p value <0.005) or TAU_ITR113 (GFAP.HL.T2A) (p value <0.05). In general, in the T2A cohort, the PT3 expression in the CSF was higher in mice treated with HL configuration genomes compared to the LH genome configuration regardless of the promoter used.

The PT3 expression obtained using cell specific promoters in various genome configurations was compared with IPN002 expression in mice using identical promoters and genome configurations (see Table 108 and Table 111 in Example 8). Regardless of the cell specific promoter used, the HLT2A genome configuration resulted in higher anti tau antibody expression (ng/mg or ab/vg) in the CNS compared to the LHT2A or HLF2A genome configurations. Overall, higher IPN002 expression than PT3 expression (ab/vg) was obtained when using similar genome configurations. In both the PT3 study (instant example) and the IPN002 (Example 8), low levels of anti-tau antibody were observed in the peripheral tissues. In general, serum antibody levels were higher when the GFAP promoter was used than when the Syn promoter was used. Within the GFAP promoter based constructs, higher antibody expression was observed within the T2A group than the F2A group. In the CSF, no significant difference was observed in IPN002 study across all genome configurations analyzed within the T2A or F2A groups. However. HLT2A configuration resulted in higher IPN002 expression compared to HLF2A configuration or LHT2A configuration.

Taken together, these studies demonstrated that the mice treated with antibody constructs comprising the HLT2A genome configuration (heavy-linker-light) demonstrated comparatively more antibody expression (ab/vg), based on functional binding ELISA.

Anti-tau antibody distribution was evaluated using anti-IgG1 antibody-immunohistochemistry using DAB for detection. Broad distribution of PT3 expression in the brain was observed in all the tested viral genome configurations except the PBS group. Cell specific expression was measured in conjunction with anti-S100β immunohistochemistry using green chromogen (S100β is used an astrocytic cell marker). Promoter specific expression was observed in the neurons or astrocytes of mice treated with the corresponding promoters.

Comparing PT3 expression (ng/mg) among ubiquitous and cell specific promoters utilizing TAU_ITR111 (Voy101.CBA.PT3.H.F.T2A.L), TAU_ITR112 (Voy101.CAG.PT3.H.F.T2A.L), TAU_ITR113 (GFAP.HL.T2A), TAU_ITR114 (SYN.HL.T2A) constructs, it was noted that ubiquitous promoters produced higher PT3 expression in the CNS compared to cell-specific promoters. However, the PT3 levels in the CSF were comparable among all 4 promoters.

Example 21. In Vivo Analysis of Constructs for Expression of Antibody Fragments IPN002 Fab Viral Genomes in Mice

To study biodistribution, tissue tropism and expression patterns of anti-tau antibody IPN002 fragments (Fab vs (Fab′)²) driven by CAG promoter in serum, CSF and/or CNS tissue of mice after intravenous delivery of AAV particles, viral genomes described in Table 171 were packaged into VOY101 capsids. AAV particles were formulated and provided intravenously at a dose of 1.4×10¹³ vg/kg into 2 month-old female C57Bl/6 mice. 28 days after administration, mice were sacrificed, perfused intracardially with PBS and CSF and/or tissue samples (hippocampus, cortex, thalamus, brain stem, spinal cord, olfactory bulb, CSF) were collected for analysis. Study design is shown in Table 171.

TABLE 171 Biodistribution of VOY101.IPN002 viral genomes (AAV genomes/cell) SEQ End TAU_ITR ID Dose Dose of AAV Particle ID NO: μL (vg/kg) (vg) Route N study IPN002.(Fab{grave over ( )})₂.CAG.HL.T2 TAU_ITR126 2176 100 1.4 × 10¹³ 2.8 × 10¹¹ IV 6 Day 28 IPN002.Fab_ext.CAG.HL.T2 TAU_ITR128 2178 100 1.4 × 10¹³ 2.8 × 10¹¹ IV 6 Day 28 IPN002.Fab_ext.CAG.LH.T2 TAU_ITR130 2180 100 1.4 × 10¹³ 2.8 × 10¹¹ IV 6 Day 28 PBS — — 100 — — IV 4 D 28

VG/DC (vector genome/diploid cell) was quantified for a subset of tissues, such as for brain, and CSF by droplet digital PCR. Antibody levels in the hippocampus, cortex, olfactory bulb, and CSF were quantified using ePHF ELISA, as described above. Vector genome biodistribution quantification (VG/DC) in brain and spinal cord are shown in Table 172 and the antibody level measurements are shown in Table 173 and Table 174. Significance was analyzed using one-way ANOVA-Tukey's multiple comparison test.

TABLE 172 Biodistribution of VOY101.IPN002 viral genomes (AAV genomes/cell) AAV Olfactory Spinal Partide Hippocampus Cortex bulb Thalamus Brainstem Cord TAU_ITR126 15.82 18.60 9.17 62.46 38.13 21.96 (IPN002.(Fab{grave over ( )})₂.CAG.HL.T2) 20.55 27.61 21.94 80.46 52.24 20.40 30.65 13.52 20.70 55.02 41.81 29.69 28.30 30.93 31.83 62.82 105.57 83.17 15.14 20.04 27.89 55.62 62.12 45.10 13.35 14.19 25.05 39.21 56.85 32.47 Average 20.63 20.82 22.76 59.27 59.45 38.80 TAU_ITR128 19.17 22.18 21.60 54.91 39.88 23.48 (IPN002.Fab_ext.CAG.HL.T2) 11.66 18.18 19.06 24.56 24.39 25.99 14.09 25.64 48.77 84.41 64.66 4.93 8.26 14.96 23.06 28.80 28.00 17.52 2.45 3.36 2.90 8.50 6.33 38.29 20.22 39.86 30.62 69.61 78.87 36.96 Average 12.64 20.70 24.33 45.13 40.36 24.53 TAU_ITR130 17.16 23.89 20.93 45.81 57.77 31.99 (IPN002.Fab_ext.CAG.LH.T2) 21.36 51.64 21.64 59.06 77.14 53.97 17.26 33.18 20.10 55.46 50.30 33.16 24.74 25.15 27.57 32.72 64.24 30.44 22.43 28.26 69.07 86.67 135.44 58.60 59.46 27.90 — 20.49 39.21 20.51 Average 27.07 31.67 31.86 50.04 70.69 38.11 PBS — 0.01 0.00 0.00 0.0 0.02

Among the Fab constructs tested, TAU_ITR130 (IPN002.Fab_ext.CAG.LH.T2) showed higher expression in all tissue types tested when compared to TAU_ITR128 (IPN002.Fab_ext.CAG.HL.T2). Among the (Fab′)2 based constructs and the Fab constructs tested, the (Fab′)2 construct TAU_ITR126 (IPN002.(Fab′)2.CAG.HL.T2) showed highest expression.

TABLE 173 IPN002 fragment expression in CNS Hippocampus Cortex Olfactory bulb ng/mg scFv/ ng/mg ng/mg Construct protein Vg protein scFv/Vg protein seFv/Vg TAU_ITR126 5.18 6.33 16.17 0.87 14.00 1.53 (IPN002.(Fab{grave over ( )})₂.CAG.HL.T2) 14.25 0.69 22.42 0.81 17.24 0.79 7.68 0.25 11.31 0.84 8.22 0.40 14.18 0.50 23.90 0.77 23.72 0.75 9.42 0.62 20.19 1.01 20.91 0.75 7.34 0.55 20.63 1.45 19.72 0.79 Average 9.68 0.49 19.10 0.96 17.30 0.83 TAU_ITR128 38.48 2.01 48.38 2.18 44.25 2.05 (IPN002.Fab_ext.CAG.HL.T2) 15.52 1.33 51.81 2.85 28.63 1.50 31.54 2.24 55.66 2.17 38.50 0.79 19.38 2.35 37.28 2.49 30.98 1.34 2.86 1.87 3.39 1.32 47.55 1.55 37.92 — 52.48 — — Average 24.28 1.96 41.50 2.20 37.98 1.45 TAU_ITR130 24.52 1.43 37.72 1.58 22.80 1.09 (IPN002.Fab_ext.CAG.LH.T2) 9.73 0.46 43.89 0.85 21.23 0.98 9.35 0.77 25.22 0.72 10.84 0.94 13.29 0.59 23.90 1.11 18.90 0.27 12.81 0.30 22.37 1.79 18.53 — 13.26 — 31.24 — 22.92 — 17.86 — 49.90 — — — Average 14.40 0.71 33.46 1.21 19.20 0.82 Vehicle 0.00 0.00 0.00 0.00 0.00 0.00 (PBS)

TABLE 174 IPN002 Fab or (Fab′)₂ expression in CSF ng/mg pM (Fab′)2 or (Fab′)2 or Construct Fab per ml Fab TAU_ITR126 43.63 392.54 (IPN002.(Fab′)₂.CAG.HL.T2) 46.48 418.18 23.94 215.38 34.56 310.96 — — — — Average 37.15 334.27 TAU_ITR128 308.03 6165.939 (IPN002.Fab_ext.CAG.HL.T2) 295.16 5908.297 343.59 6877.729 208.77 4179.039 Average 288.89 5782.751 TAU_ITR130 189.14 3786.026 (IPN002.Fab_ext.CAG.LH.T2) 192.19 3847.162 129.36 2589.520 211.61 4235.808 172.12 3445.415 212.26 4248.908 Average 184.45 3692.140 Vehicle (PBS) 0.00 0.00

Among the Fab constructs. HL based construct TAU_ITR128 (IPN002.Fab_ext.CAG.HL.T2), appeared to have higher expression compared to TAU_ITR130 (IPN002.Fab_ext.CAG.LH.T2).

Immunohistochemistry using anti-Kappa antibody was performed on brain tissue of mice treated with an IV bolus injection of ssVOY101.IPN002 AAV particles comprising viral genomes encoding (Fab′)₂ or Fab, driven by CAG promoters 28 days prior. Broad distribution of IPN002 (Fab′)₂ or Fab antibody delivered by VOY101 using CAG promoter with the configurations described in Table 171 was observed both in the CNS and in the spinal cord. Stronger staining in multiple CNS regions was detected with TAU_ITR128 (IPN002.Fab_ext.CAG.HL.T2) as compared to the other constructs listed in Table 171.

Localization studies showed that all three constructs listed in Table 171 were distributed to both neurons and astrocytes.

PT3 Fab Viral Genomes in Mice

To study the biodistribution, tissue tropism and expression of anti-tau antibody PT3 fragments (Fab and (Fab)₂) in serum, CSF and/or CNS tissue of mice after intravenous delivery of AAV particles, viral genomes described in Table 175 were packaged into VOY101 capsids. AAV particles were formulated and provided intravenously at a dose of 1.4×10¹³ vg/kg to 2 month-old female C57Bl/6 mice. Twenty-eight days after administration, mice were sacrificed, perfused intracardially with PBS and CSF and/or tissue samples (hippocampus, cortex, thalamus, brain stem, spinal cord, olfactory bulb, CSF) were collected for analysis. Study design is shown in Table 175.

TABLE 175 PT3 Fab/F(ab{grave over ( )})₂ IV study design SEQ End TAU_ITR ID Dose ~Dose of Construct Configuration ID NO: μl VG/kg Vg Route N study CAG PT3_Fab H.F.T2A.L TAU_ITR180 2230 100 1.4E13 2.8E11 IV 6 D 28 SYN.PT3_Fab H.F.T2A.L TAU_ITR188 2260 100 1.4E13 2.8E11 IV 6 D 28 GFAP.PT3_Fab H.F.T2A.L TAU_ITR189 2261 100 1.4E13 2.8E11 IV 6 D 28 CAG PT3_F(ab′)₂ TAU_ITR190 2262 100 1.4E13 2.8E11 IV 6 D 28 H.hIgG3_3Hinge.F.T2A.L SYN.PT3_F(ab′)2 TAU_ITR191 2263 100 1.4E13 2.8E11 IV 6 D 28 H.hIgG3_3Hinge.F.T2A.L GFAP.PT3_F(ab′)₂ TAU_ITR192 2264 100 1.4E13 2.8E11 IV 6 D 28 H.hIgG3_3Hinge.F.T2A.L CAG PT3_F(ab′)₂ TAU_ITR193 2265 100 1.4E13 2.8E11 IV 6 D 28 H.hIgG3_3Hinge.F.F2A.L SYN PT3_F(ab′)₂ TAU_ITR194 2266 100 1.4E13 2.8E11 IV 6 D 28 H.hIgG3_3Hinge.F.F2A.L GFAP PT3_F(ab′)₂ TAU_ITR195 2267 100 1.4E13 2.8E11 IV 6 D 28 H.hIgG3_3Hinge.F.F2A.L PBS — — 100 — IV 8 D 28

Vector genome was quantified for a subset of tissues, such as for brain, spinal cord, CSF, serum, and liver by droplet digital PCR and normalized per diploid cell (VG/DC) using the endogenous mouse transferrin receptor C gene (TFRC). Antibody levels in the tissues were quantified using ePHF ELISA, as described above. For these experiments, an anti-kappa-HRP was used as the detection antibody in the ePHF ELISA and a recombinant PT3 Fab or F(ab′)2 was used as a standard. Vector genome biodistribution quantification (VG/DC) in brain and spinal cord are shown in Table 176 and the antibody level measurements are shown in Table 177 and Table 178. Significance was analyzed using one-way ANOVA-Tukey's multiple comparison test. The results were also compared to the data obtained by transducing rodents with scFv constructs described in Table 153. Table 154. Table 155, and Table 156.

TABLE 176 Biodistribution of VOY101.PT3 viral genomes (AAV genomes/cell) Construct Configuration Olfactory Spinal (TAU_ITR ID) Cortex Hippocampus Bulb Cord Vehicle 0.00 0.00 0.00 0.00 GFAP.F(ab′)₂.HL.T2A 59.66 96.407 93.93 175.95 (TAU_ITR192) 25.84 16.215 58.22 90.17 35.97 34.999 41.80 77.01 13.17 17.486 33.98 30.39 36.06 65.657 82.67 133.80 36.49 39.704 57.63 76.65 Average 34.53 45.08 61.37 97.33 SYN.F(ab′)₂.HL.T2A 25.76 29.356 33.32 62.15 (TAU_ITR191) 33.72 65.259 72.73 35.69 35.29 31.863 45.38 114.84 31.71 40.863 72.96 123.35 34.91 44.189 51.50 97.39 41.11 39.333 56.87 67.66 Average 33.75 41.81 55.46 83.51 CAG.F(ab′)₂.HL.T2A 18.00 16.861 16.48 86.92 (TAU_ITR190) 15.22 14.334 15.21 81.93 9.27 15.698 31.06 52.76 11.63 15.610 15.22 11.52 13.11 6.386 15.25 18.41 11.39 8.523 13.57 19.78 Average 13.10 12.90 17.80 45.22 CAG.F(ab′)₂.HL.F2A 28.54 32.441 73.48 110.55 (TAU_ITR193) 23.40 20.576 52.51 103.39 36.16 37.218 69.30 127.66 34.23 29.131 37.18 66.41 27.94 33.222 57.25 73.27 44.03 34.568 50.42 106.80 Average 32.38 31.19 56.69 98.01 SYN.Fab.HL.T2A 20.06 11.107 27.75 35.30 (TAU_ITR188) 30.05 28.200 46.34 122.48 60.13 82.673 63.78 30.90 57.01 59.839 81.80 307.92 34.60 62.331 67.39 112.09 44.07 25.380 151.00 160.08 Average 40.99 44.92 73.01 128.13 CAG.Fab.HL.T2A 38.22 110.961 42.12 35.75 (TAU_ITR180) 15.13 20.688 25.32 47.77 16.55 18.755 51.72 61.31 17.98 10.043 31.93 50.11 22.51 24.999 26.60 55.10 30.71 50.367 45.16 91.20 12.00 16.332 15.08 53.24 Average 21.87 36.02 33.99 56.36 GFAP.F(ab′)₂.HL.F2A 21.62 20.987 35.76 40.35 (TAU_ITR195) 27.14 108.730 66.79 113.01 39.12 66.121 168.32 176.09 22.65 48.241 34.40 45.45 42.00 77.394 47.39 82.56 19.74 46.927 63.92 81.14 Average 28.71 61.40 69.43 89.77 SYN.F(ab′)₂.HL.F2A 21.77 61.32 47.43 78.25 (TAU_ITR194) 38.78 73.78 49.62 143.28 36.45 42.48 79.82 87.14 57.30 102.33 136.96 155.97 27.85 85.72 97.86 116.69 24.01 55.63 54.33 51.00 Average 34.36 70.21 77.67 105.39 GFAP.Fab.HL.T2A 50.64 56.364 63.86 127.32 (TAU_ITR189) 51.51 58.083 108.95 60.53 49.01 79.911 130.12 165.26 40.72 53.395 125.42 97.73 43.82 55.946 66.42 109.34 29.67 51.120 61.83 73.39 Average 44.23 59.14 92.77 105.59

As shown in Table 176, among the constructs with a T2A cleavage site, constructs with GFAP and SYN promoters generally showed higher AAV biodistribution than constructs operably linked to a CAG promoter. For transgenes with F2A peptide cleavage sites, this trend is only observed in hippocampal tissue. Delivery of Fab constructs (TAU_ITR180, TAU_ITR189 and TAU_ITR188) yielded the highest AAV genomes per cell, as compared to F(ab′)2 or scFv constructs comprising the same promoter (e.g., CAG.Fab resulted in more AAV genomes per cell than CAG. F(ab′)2 or CAG.scFv).

Using One-way ANOVA-Tukey's multiple comparison test, statistical analyses were performed for AAV distribution of each form of fragment (Fab, F(ab′)2, and scFv) driven by each promoter and in each tissue. Assessment of biodistribution in the cortex yielded the following statistically significant relationships. In comparing constructs encoding Fab fragments, administration of TAU_ITR189 (GFAP.Fab) and TAU_ITR188 (SYN.Fab) resulted in significantly more AAV genomes per cell as compared to TAU_ITR180 (CAG.Fab) (p values <0.0005 and <0.005 respectively). For the F(ab′)2 fragment group, a similar pattern was evident, with delivery of TAU_ITR192 (GFAP. F(ab′)₂) generating significantly more AAV genomes per cell in the cortex than delivery of TAU_ITR190 (CAG. F(ab′)2) (p value <0.005). In comparing biodistribution of constructs encoding scFv fragments (TAU_ITR162. TAU_ITR165, and TAU_ITR168; Table 154), delivery of TAU_ITR165 (GFAP.scFv) resulted in greater biodistribution to the cortex than delivery of TAU_ITR162 (CAG.scFv) (p value <0.05). Comparisons across fragment type with expression driven by the same promoter showed significantly greater biodistribution to the cortex and the hippocampus following delivery of TAU_ITR188 (SYN.Fab) than TAU_ITR168 (SYN.scFv) (p value <0.005) and significantly greater biodistribution to cells of the hippocampus subsequent to delivery of TAU_ITR192 (GFAP. F(ab′)₂) than TAU_ITR165 (GFAP.scFv) (p value <0.05).

Antibody levels in the various tissues were quantified using ePHF ELISA, as described above, but using an anti-Kappa-HRP as a detection antibody The antibody level measurements in the cortex, hippocampus, olfactory bulb, and spinal cord are shown in Table 177 and Table 178. Significance was analyzed using one-way ANOVA-Tukey's multiple comparison test.

TABLE 177 PT3 Fab/F(ab′)₂ expression (ng/mg) Construct Olfactory Spinal (TAU_ITR ID) Cortex Hippocampus Bulb Cord Vehicle 0.00 1.69 0.00 0.00 CAG.F(ab′)₂.HL.F2A 7.30 0.00 25.66 67.08 (TAU_ITR.193) 12.99 7.50 26.31 76.64 15.36 10.92 43.98 65.61 8.45 6.57 37.95 42.91 22.62 11.19 36.26 95.39 20.20 14.09 66.37 85.58 Average 14.49 8.38 39.42 72.20 SYN.Fab.HL.T2A 0.51 −0.22 0.00 0.00 (TAU_ITR188) 10.97 10.13 32.01 234.75 6.88 9.58 36.81 182.59 28.19 36.04 70.50 363.45 7.05 10.02 25.76 185.08 16.67 32.51 90.01 391.81 Average 11.71 16.34 42.51 226.28 CAG.Fab.HL.T2A 213.95 152.15 246.17 400.88 (TAU_ITR180) 37.26 30.67 184.38 180.63 106.69 71.19 196.59 297.40 51.67 45.98 252.33 374.69 42.30 30.46 158.28 141.95 128.16 92.23 261.18 284.72 24.33 15.50 129.56 139.25 Average 86.34 62.60 204.07 259.93 GFAP.F(ab′)₂.HL.F2A 0.00 0.00 0.00 0.00 (TAU_ITR195) 0.00 0.00 18.25 9.85 3.18 0.00 22.67 11.22 0.00 0.00 13.02 12.81 3.87 0.00 47.61 29.23 0.00 0.00 14.03 9.43 Average 1.18 0.00 19.26 12.09 SYN.F(ab′)₂.HL.F2A 0.00 0.00 0.00 45.63 (TAU_ITR194) 0.00 0.00 0.00 37.95 0.00 0.00 0.00 67.24 0.00 0.00 9.28 83.39 0.00 0.00 9.78 76.17 0.00 0.00 — 62.03 Average 0.00 0.00 3.81 62.07 GFAP.Fab.HL.T2A 17.63 12.07 123.89 38.49 (TAU_ITR189) 42.89 14.45 221.26 58.23 29.03 22.36 262.50 112.04 14.59 12.94 119.80 74.22 27.13 10.66 154.62 90.98 48.47 15.16 234.40 108.85 Average 29.96 14.61 186.08 80.47 GFAP.F(ab′)₂.HL.T2A 3.87 0.00 48.19 57.72 (TAU_ITR192) 0.00 0.00 28.06 22.84 6.17 0.00 43.30 38.07 0.00 0.00 0.00 7.36 5.28 0.00 0.00 46.19 4.27 0.00 24.68 52.93 Average 3.27 0.00 24.04 37.52 SYN.F(ab′)₂.HL.T2A 2.70 0.00 9.40 128.50 (TAU_ITR191) 0.00 0.00 11.47 87.30 3.10 0.00 14.70 124.64 3.29 0.00 12.12 229.45 3.55 0.00 16.95 157.90 2.97 0.00 11.61 185.24 Average 2.60 0.00 12.71 152.17 CAG.F(ab′)₂.HL.T2A 2.66 0.00 13.09 53.44 (TAU_ITR190) 3.41 6.28 12.53 61.70 3.74 0.00 8.86 73.11 2.61 0.00 10.77 48.82 3.67 0.00 22.19 92.71 3.81 0.00 13.06 139.20 Average 3.32 1.05 13.42 78.16

As shown in Table 177, high levels of PT3 Fab were observed in the hippocampus, cortex and olfactory bulb of the mice dosed with Fab constructs as compared to mice dosed with F(ab′)₂ constructs. In contrast to the vector genome quantification data, use of a CAG promoter appeared to drive higher expression when compared to constructs comprising a cell specific promoter. High levels of PT3 Fab were also observed in the olfactory bulb of the mice dosed with Fab constructs as compared to those dosed with F(ab′)2 vectors. PT3 expression (ng/mg) was significantly higher (p value <0.0005) in the cortex of rodents transduced with CAG.Fab.HL.T2A (TAU_ITR180) when compared to the expression in the cortex of rodents transduced with SYN.Fab.HL.T2A (TAU_ITR188) or ssAAV CAG PT3 VL G4S-3 VH HA rBGpA (TAU_ITR162). PT3 expression (ng/mg) was significantly higher (p value <0.005) in the cortex of rodents transduced with CAG.Fab.HL.T2A (TAU_ITR180) when compared to the expression in the cortex of rodents transduced with GFAP.Fab.HL.T2A (TAU_ITR189) or CAG.F(ab′)2.HL.T2A (TAU_ITR190). In the hippocampus, PT3 expression (ng/mg) was significantly higher, p value <0.0005, in the rodents transduced with CAG.Fab.HL.T2A (TAU_ITR180) compared to SYN.Fab.HL.T2A (TAU_ITR188). GFAP.Fab.HL.T2A (TAU_ITR189), or ssAAV CAG PT3 VL G4S-3 VH HA rBGpA (TAU_ITR162). PT3 expression (ng/mg) was also significantly higher (p value <0.005) in the hippocampus of rodents transduced with CAG.Fab.HL.T2A (TAU_ITR180) compared to rodents transduced with CAG.F(ab′)2.HL.T2A (TAU_ITR190).

In spinal cord, PT3 expression levels were similar when driven by CAG or SYN promoter, regardless of whether the PT3 fragment was Fab or F(ab′)₂.

TABLE 178 Normalized PT3 Fab/F (ab′)2 expression (PT3/vector genome) Construct Olfactory Spinal (TAU_ITR ID) Cortex Hippocampus Bulb cord Vehicle 0 0 0 0 CAG.F(ab′)₂.HL.F2A 0.26 0.00 0.35 0.61 (TAU_ITR193) 0.56 0.36 0.50 0.74 0.42 0.29 0.63 0.51 0.25 0.23 1.02 0.65 0.81 0.34 0.63 1.30 0.46 0.41 1.32 0.80 Average 0.46 0.27 0.74 0.77 SYN.Fab.HL.T2A 0.03 0.00 0.00 0.00 (TAU_ITR188) 0.37 0.36 0.69 1.92 0.11 0.12 0.58 5.91 0.49 0.60 0.86 1.18 0.20 0.16 0.38 1.65 0.38 1.28 0.60 2.45 Average 0.26 0.42 0.52 2.18 CAG.Fab.HL.T2A 5.60 1.37 5.84 11.21 (TAU_ITR180) 2.46 1.48 7.28 3.78 6.45 3.80 3.80 4.85 2.87 4.58 7.90 7.48 1.88 1.22 5.95 2.58 4.17 1.83 5.78 3.12 20.3 0.95 8.59 2.62 Average 3.64 2.18 6.45 5.09 GFAP.F(ab′)₂.HL.F2A 0.00 0 0.00 0.00 (TAU_ITR195) 0.00 0 0.27 0.09 0.08 0 0.13 0.06 0.00 0 0.38 0.28 0.09 0 1.00 0.35 0.00 0 0.22 0.12 Average 0.03 0.00 0.34 0.15 0.00 0 0.00 0.58 0.00 0 0.00 0.26 SYN.F(ab′)₂.HL.F2A 0.00 0 0.00 0.77 (TAU_ITR194) 0.00 0 0.07 0.53 0.00 0 0.10 0.65 0.00 0 0.00 1.22 Average 0.00 0.00 0.03 0.67 GFAP.Fab.HL.T2A 0.35 0.21 1.94 0.30 (TAU_ITR189) 0.83 0.25 2.03 0.96 0.59 0.28 2.02 0.68 0.36 0.24 0.96 0.76 0.62 0.19 2.33 0.83 1.63 0.30 3.79 1.48 Average 0.73 0.25 2.18 0.84 GFAP.F(ab′)₂.HL.T2A 0.06 0 0.51 0.33 (TAU_ITR192) 0.00 0 0.48 0.25 0.17 0 1.04 0.49 0.00 0 0.00 0.24 0.15 0 0.00 0.35 0.12 0 0.43 0.69 Average 0.08 0.00 0.41 0.39 SYN.F(ab′)₂.HL.T2A 0.10 0 0.28 2.07 (TAU_ITR191) 0.00 0 0.16 2.45 0.09 0 0.32 1.09 0.10 0 0.17 1.86 0.10 0 0.33 1.62 0.07 0 0.20 2.74 Average 0.08 0.00 0.24 1.97 CAG.F(ab′)₂.HL.T2A 0.15 0.00 0.79 0.61 (TAU_ITR190) 0.22 0.44 0.82 0.75 0.40 0.00 0.29 1.39 0.22 0.00 0.71 4.24 0.28 0.00 1.45 5.03 0.33 0.00 0.96 7.04 Average 0.27 0.07 0.84 3.18

As shown in Table 178, inclusion of the CAG promoter resulted in higher PT3 expression in TAU_ITR180 (CAG PT3_Fab H.F.T2A.L), TAU_ITR190 (CAG PT3_F(ab′)2 H.hIgG3_3Hinge.F.T2A.L), TAU_ITR193 (CAG PT3_F(ab′)2 H.hIgG3_3Hinge.F.F2A.L) regardless of whether Fab or F(ab′)₂ antibody fragments were delivered to the cortex, hippocampus and olfactory bulb. In the spinal cord, CAG promoter appeared to drive PT3 expression in TAU_ITR180 (CAG PT3_Fab H.F.T2A.L), TAU_ITR190 (CAG PT3_F(ab′)2 H.hIgG3_3Hinge.F.T2A.L), TAU_ITR193 (CAG PT3_F(ab′)2 H.hIgG3_3Hinge.F.F2A.L) at levels similar to that seen with the SYN promoter constructs TAU_ITR188 (SYN.PT3_Fab H.F.T2A.L), TAU_ITR191 (SYN.PT3_F(ab′)2 H.hIgG3_3Hinge.F.T2A.L), TAU_ITR194 (SYN PT3_F(ab′)2 H.hIgG3_3Hinge.F.F2A.L). Comparing Fab and F(ab′)2 constructs operably linked to the same promoter, it was noted that PT3 Fab constructs (TAU_ITR180, TAU_ITR188, TAU_ITR189) resulted in higher expression per vector genome as compared to PT3 F(ab′)2 constructs (TAU_ITR190, TAU_ITR191, TAU_ITR192, TAU_ITR193, TAU_ITR194, TAU_ITR195).

Normalization of antibody fragments level showed a highest average level of expression per vector genome in the group dosed with CAG-Fab (TAU_ITR180). The statistical significance of the data in Table 178 was analyzed using one-way ANOVA-Tukey's multiple comparison test. Normalized PT3 expression (ab/vg) was significantly higher (p<0.0005) in the cortex of the former of the following pairs of comparison compared to the latter, (a) CAG PT3_Fab H.F.T2A.L (TAU_ITR180) compared to CAG PT3_F(ab′)2 H.hIgG3_3Hinge.F.T2A.L (TAU_ITR190), GFAP.PT3_Fab H.F.T2A. L (TAU_ITR189), or SYN.PT3_Fab H.F.T2A.L (TAU_ITR188) (b) ssAAV CAG PT3 VL G4S-3 VH HA rBGpA (TAU_ITR162) compared to ssAAV SYN PT3 VL G4S-3 VH HA rBGpA (TAU_ITR168) or ssAAV GFAP PT3 VL G4S-3 VH HA rBGpA (TAU_ITR165) or CAG PT3_F(ab′)2 H.hIgG3_3Hinge.F.T2A.L (TAU_ITR190). In the hippocampus, normalized PT3 expression (ab/vg) was significantly higher (p value <0.0005) in CAG PT3_Fab H.F.T2A.L (TAU_ITR180) compared to CAG PT3_F(ab′)2 H.F.T2A.L (TAU_ITR190), ssAAV CAG PT3 VL G4S-3 VH HA rBGpA (TAU_ITR162), SYN.PT3_Fab H.F.T2A.L (TAU_ITR188), or GFAP.PT3_Fab H.F.T2A.L (TAU_ITR189).

Antibody levels in the CSF, serum and liver tissues were also quantified using ePHF ELISA, as described above and as shown in Table 179. Also included in the table are vector genome quantification of the biodistribution to the liver (VG/DC).

TABLE 179 PT3 expression in CSF serum and liver CSF CSF Serum Serum Liver Liver Description (ng/ml) (nM) (ng/ml) (nM) CVG/DC) (ng/mg) CAG.F(ab′)₂.HL.F2A 95.4 0.87 306.50 2.79 3.07 21.30 (TAU_ITR193) 101.55 0.92 6248.75 56.81 3.93 20.32 70.25 0.64 5193.75 47.22 4.75 36.75 46.45 0.42 5420.75 49.28 3.11 25.63 97.15 0.88 12421.50 112.92 5.80 34.15 — — 11130.25 101.18 7.30 67.69 — — 13131.00 119.37 — — Average 82.16 0.75 7693.21 69.94 4.66 34.32 SYN.PT3_Fab H.F.T2A.L 340.65 6.19 3479.73 63.27 0.30 0.00 (TAU_ITR188) 678.10 12.33 800.91 14.56 10.50 0.00 663.75 12.07 871.53 15.85 6.98 0.00 — — 743.96 13.53 3.48 0.00 — — 2094.76 38.09 4.09 0.00 — — 447.84 8.14 4.78 0.00 Average 560.83 10.20 1406.45 25.57 5.02 0.00 CAG PT3_Fab H.F.T2A.L 1077.65 19.59 2701.37 49.12 5.67 17.07 (TAU_ITR180) 703.40 12.79 7146.70 129.94 1.65 8.21 894.50 16.26 4679.73 85.09 4.56 18.86 903.90 16.43 2199.09 39.98 3.74 59.20 833.20 15.15 2513.21 45.69 6.34 0.00 1026.80 18.67 2270.84 41.29 4.48 51.66 — — — — 2.58 11.89 Average 906.58 16.48 3585.16 65.18 4.15 23.84 GFAP.F(ab′)₂.HL.F2A 0.00 0.00 274.00 2.49 0.63 0.00 (TAU_ITR195) 0.00 0.00 808.25 7.35 4.96 7.12 0.00 0.00 3426.00 31.15 9.12 19.29 0.00 0.00 414.75 3.77 2.58 3.39 0.00 0.00 2556.00 23.24 7.52 15.07 — — 1057.75 9.62 4.00 10.46 Average 0.00 0.00 1422.79 12.93 4.80 9.22 SYN.F(ab′)₂.HL.F2A 66.60 0.61 195.00 1 77 4.54 0.00 (TAU_ITR194) — — 306.50 2.79 4.55 0.00 — — 243.50 2.21 4.05 0.00 104.05 0.95 448.75 4.08 9.29 0.00 106.40 0.97 364.75 3.32 7.72 0.00 84.95 0.77 267.50 2.43 4.39 0.00 Average 90.50 0.82 304.33 2.77 5.76 0.00 GFAP.PT3_Fab 484.75 8.81 1300.38 23.64 7.36 11.21 H.F.T2A.L (TAU_ITR189) 234.65 4.27 3106.15 56.48 4.82 13.02 654.35 11.90 1185.88 21.56 6.27 12.32 443.60 8.07 5381.78 97.85 4.44 7.05 956.35 17.39 3069.70 55.81 3.89 4.47 — — 1196.36 21.75 7.41 5.66 Average 554.74 10.09 2540.04 46.18 5.70 8.96 GFAP.PT3_F(ab′)2 59.05 0.54 830.50 7.55 7.14 14.42 H.hIgG3_3Hinge.F.T2A.L 51.10 0.46 967.75 8.80 10.11 61.18 (TAU_ITR192) 68.10 0.62 704.75 6.41 8.79 12.44 41.80 0.38 65.75 0.60 0.56 2.66 90.45 0.82 1085.25 9.87 4.68 13.27 52.50 0.48 704.75 6.41 5.01 35.44 Average 60.50 0.55 726.46 6.60 6.05 23.24 SYN.PT3_F(ab′)2 33.90 0.31 310.25 2.82 4.31 0.00 H.hIgG3_3Hinge.F.T2A.L 120.95 1.10 311.75 2.83 3.08 0.00 (TAU_ITR191) 83.05 0.76 323.50 2.94 5.33 0.00 113.65 1.03 164.00 1.49 4.54 0.00 34.80 0.32 316.65 2.88 8.14 0.00 102.25 0.93 296.25 2.69 6.80 0.00 Average 81.43 0.74 287.07 2.61 5.37 0.00 45.30 0.41 2599.75 23.63 5.75 21.25 CAGPT3_F(ab′)2 60.15 0.55 2990.75 27.19 7.73 81.32 H.hIgG3_3Hinge.F.T2A.L 64.75 0.59 2693.75 24.49 4.33 28.72 (TAU_ITR190) 54.70 0.50 2119.50 19.27 2.40 15.47 53.80 0.49 1746.50 15.88 6.07 18.05 74.05 0.67 3126.50 28.42 3.97 22.46 Average 58.79 0.53 2546.13 23.15 5.04 31.21 Vehicle 0.00 0.00 0.00 0.00 0.00 0.00

Consistent with the measurements in Table 177 and Table 178, higher PT3 expression levels were observed with Fab constructs (TAU_ITR180, TAU_ITR188, TAU_ITR189) compared to F(ab′)₂ constructs (TAU_ITR190, TAU_ITR191, TAU_ITR192, TAU_ITR193, TAU_ITR194, TAU_ITR195) and lowest with delivery of F(ab′)2 constructs. Among the Fab constructs, CSF PT3 fragment expression levels were the same regardless of the promoter used. In the group of mice dosed with the F(ab′)₂ T2A vectors (TAU_ITR190, TAU_ITR191, TAU_ITR192), no significant difference in the expression of PT3 was detected among the different promoters. In the serum, as expected, the CAG promoter appeared to drive the highest expression of PT3 in constructs (TAU_ITR180 (CAG PT3_Fab H.F.T2A.L), TAU_ITR190 (CAG PT3_F(ab′)2 H.hIgG3_3Hinge.F.T2A.L), TAU_ITR193 (CAG PT3_F(ab′)2 H.hIgG3_3Hinge.F.F2A.L)), whereas the SYN promoter had the least expression in constructs (TAU_ITR188 (SYN.PT3_Fab H.F.T2A.L), TAU_ITR191 (SYN.PT3_F(ab′)2 H.hIgG3_3Hinge.F.T2A.L), TAU_ITR194 (SYN PT3_F(ab′)2 H.hIgG3_3Hinge.F.F2A.L)). In the liver, all the constructs resulted in similar AAV biodistribution albeit at levels lower than seen in the CNS tissues. PT3 antibody expression was observed in mice transduced with CAG promoter constructs (TAU_ITR180 (CAG PT3_Fab H.F.T2A.L), TAU_ITR190 (CAG PT3_F(ab′)2 H.hIgG3_3Hinge.F.T2A.L),TAU_ITR193 (CAG PT3_F(ab′)2 H.hIgG3_3Hinge.F.F2A.L)) and to a lesser extent the GFAP promoter constructs (TAU_ITR189 (GFAP.PT3_Fab H.F.T2A.L), TAU_ITR192 (GFAP.PT3_F(ab′)2 H.hIgG3_3Hinge.F.T2A.L), TAU_ITR195 (GFAP PT3_F(ab′)2 H.hIgG3_3Hinge.F.F2A.L)). No PT3 expression was evident in the liver when driven by the synapsin promoter (TAU_ITR188 (SYN.Fab), TAU_ITR191 (SYN. F(ab′)2), TAU_ITR168 (SYN.scFv)).

The statistical significance of the data in Table 179 was analyzed using one-way ANOVA-Tukey's multiple comparison test. PT3 expression (for both ng/ml and nM) was significantly higher (p<0.0005) in the CSF of the former of the following pairs when compared to the latter, (a) CAG PT3_Fab H.F.T2A.L (TAU_ITR180) compared to CAG PT3_F(ab′)2 H.hIgG3_3Hinge.F.T2A.L (TAU_ITR190), ssAAV CAG PT3 VL G4S-3 VH HA rBGpA (TAU_ITR162), GFAP.PT3_Fab H.F.T2A.L (TAU_ITR189) or SYN.PT3_Fab H.F.T2A.L (TAU_ITR188) (b) GFAP.PT3_Fab H.F.T2A.L (TAU_ITR189) compared to GFAP.PT3_F(ab′)2 H.hIgG3_3Hinge.F.T2A.L (TAU_ITR192) or ssAAV GFAP PT3 VL G4S-3 VH HA rBGpA (TAU_ITR165); (c) SYN.PT3_Fab H.F.T2A.L (TAU_ITR188) compared to SYN.PT3_F(ab′)2 H.hIgG3_3Hinge.F.T2A.L (TAU_ITR191), or ssAAV SYN PT3 VL G4S-3 VH HA rBGpA (TAU_ITR168). PT3 expression (nM) was also significantly higher (p<0.005 and <0.05 respectively) in the CSF of the former of the following pairs (a) CAG PT3_F(ab′)2 H.hIgG3_3Hinge.F.T2A.L (TAU_ITR190), compared to ssAAV CAG PT3 VL G4S-3 VH HA rBGpA (TAU_ITR162) (b) ssAAV CAG PT3 VL G4S-3 VH HA rBGpA (TAU_ITR162) compared to ssAAV SYN PT3 VL G4S-3 VH HA rBGpA (TAU_ITR168).

In the serum, PT3 expression (ng/ml) was significantly higher with a value of P<0.0005 in the serum of rodents transduced with CAG PT3_Fab H.F.T2A.L (TAU_ITR180) compared to ssAAV CAG PT3 VL G4S-3 VH HA rBGpA (TAU_ITR162). Higher PT3 expression (ng/ml) with a significance of p value <0.005 was observed in the PT3 in the serum of rodents treated with the former constructs in the following pairs compared to the latter constructs (a) CAG PT3_Fab H.F.T2A.L (TAU_ITR180) compared to CAG PT3_F(ab′)2 H.hIgG3_3Hinge.F.T2A.L (TAU_ITR190) (b) CAG PT3_F(ab′)2 H.hIgG3_3Hinge.F.T2A.L (TAU_ITR190) compared to SYN.PT3_F(ab′)2 H.hIgG3_3Hinge.F.T2A.L (TAU_ITR191) (c) ssAAV CAG PT3 VL G4S-3 VH HA rBGpA (TAU_ITR162) compared to ssAAV SYN PT3 VL G4S-3 VH HA rBGpA (TAU_ITR168) (d) GFAP.PT3_Fab H.F.T2A.L (TAU_ITR189) compared to ssAAV GFAP PT3 VL G4S-3 VH HA rBGpA (TAU_ITR165). Higher PT3 expression (ng/ml) (p value <0.05) was observed in the PT3 in the serum of rodents transduced with the former constructs in the following pairs compared to the latter constructs (a) CAG PT3_F(ab′)2 H.hIgG3_3Hinge.F.T2A.L (TAU_ITR190) compared to GFAP.PT3_F(ab′)2 H.hIgG3_3Hinge.F.T2A.L (TAU_ITR192) and (b) GFAP.PT3_Fab H.F.T2A.L (TAU_ITR189) compared to GFAP.PT3_F(ab′)2 H.hIgG3_3Hinge.F.T2A.L (TAU_ITR192). In comparing the PT3 expression (nM), the expression was significantly higher (p<0.0005) in CAG PT3_Fab H.F.T2A.L (TAU_ITR180) compared to ssAAV CAG PT3 VL G4S-3 VH HA rBGpA (TAU_ITR162) or SYN.PT3_Fab H.F.T2A.L (TAU_ITR188). A significance of p value <0.005 was obtained when the PT3 expression (nM) in the serum was compared between the former of the following pairs compared to the latter (a) CAG PT3_Fab H.F.T2A.L (TAU_ITR180) compared to CAG PT3_F(ab′)2 H.hIgG3_3Hinge.F.T2A.L (TAU_ITR190); (b) ssAAV CAG PT3 VL G4S-3 VH HA rBGpA (TAU_ITR162) compared to ssAAV SYN PT3 VL G4S-3 VH HA rBGpA (TAU_ITR168) (c) GFAP.PT3_Fab H.F.T2A.L (TAU_ITR189) compared to GFAP.PT3_F(ab′)2 H.hIgG3_3Hinge.F.T2A.L (TAU_ITR192) (d) GFAP.PT3_F(ab′)2 H.hIgG3_3Hinge.F.T2A.L (TAU_ITR192) compared to ssAAV GFAP PT3 VL G4S-3 VH HA rBGpA (TAU_ITR165). In general, antibody levels were highest following delivery of constructs encoding Fab fragments, followed by F(ab′)2. Expression driven by the CAG promoter resulted in the highest expression of antibody fragment in the serum, as compared to when driven by cell-specific promoters.

Immunohistochemistry (using DAB and an anti-kappa light chain primary antibody) was performed on brain tissue of mice treated with an IV bolus injection of VOY101.PT3 AAV particles comprising viral genomes encoding (Fab′)₂ or Fab, driven by CAG, SYN or GFAP promoters 28 days prior.

Comparing the PT3 Fab fragment-based constructs namely GFAP.Fab.HL.T2A (TAU_ITR189), SYN.Fab.HL.T2A (TAU_ITR188), CAG.Fab.HL.T2A (TAU_ITR180), a broad distribution of PT3 Fab fragment was observed in mice dosed with PT3 Fab vectors under CAG or cell specific promoters. Broad distribution of PT3 Fab fragment was observed from anterior to posterior coronal sections of the brain (e.g., hippocampus) of mice dosed with CAG or cell specific promoter.

PT3 F(ab′)2 T2A fragment-based constructs, namely GFAP.F(ab′)2.HL.T2A (TAU_ITR192), SYN.F(ab′)2.HL.T2A (TAU_ITR191), and CAG.F(ab′)2.HL.T2A (TAU_ITR190), also showed a broad distribution of PT3 F(ab′)2 fragment.

Strong staining was observed in multiple CNS regions in all groups dosed with vectorized Fab, but overall, CAG PT3 Fab or PT3 F(ab′)2 (F2A vectors) showed stronger signal in the brain when compared to the other constructs in Table 175 with cell specific promoters. Vehicle treated control animals showed low background levels of staining.

Taken together, these data show that constructs operably linked to the CAG promoter namely TAU_ITR180 (CAG PT3_Fab H.F.T2A.L), TAU_ITR190 (CAG PT3_F(ab′)2 H.hIgG3_3Hinge.F.T2A.L),TAU_ITR193 (CAG PT3_F(ab′)2 H.hIgG3_3Hinge.F.F2A.L) showed stronger signal in the brain when compared to those wherein expression is driven by cell specific promoters namely constructs TAU_ITR188 (SYN.PT3_Fab H.F.T2A.L).TAU_ITR191 (SYN.PT3_F(ab′)2 H.hIgG3_3Hinge.F.T2A.L), TAU_ITR194 (SYN PT3_F(ab′)2 H.hIgG3_3Hinge.F.F2A.L), TAU_ITR189 (GFAP.PT3_Fab H.F.T2A.L), TAU_ITR192 (GFAP.PT3_F(ab′)2 H.hIgG3_3Hinge.F.T2A.L), TAU_ITR195 (GFAP PT3_F(ab′)2 H.hIgG3_3Hinge.F.F2A.L).

The cell-specificity of the expression of the constructs described in Table 175 was also evaluated. Among the PT3 Fab constructs GFAP.Fab.HL.T2A (TAU_ITR189). SYN.Fab.HL.T2A (TAU_ITR188), and CAG.Fab.HL.T2A (TAU_ITR180) PT3 expression was detected in cells with neuronal and glial cell morphology in the hippocampus, cortex, thalamus and the spinal cord when a CAG promoter was used. PT3 Fab expression was most evident in cells with astrocytic morphology in cortex. PT3 Fab fragment expression was also detected in cells with neuronal or glial cell morphology in indicated brain regions when Syn or GFAP promoters were used, respectively. For viral genomes comprising a CAG promoter, PT3 Fab fragment expression was most evident in cells with astrocytic morphology in cortex. Further, PT3 Fab T2A constructs GFAP.Fab.HL.T2A (TAU_ITR189), SYN.Fab.HL.T2A (TAU_ITR188), and CAG.Fab.HL.T2A (TAU_ITR180) appeared to have higher expression when compared to other F(ab′)2 constructs (GFAP.F(ab′)2.HL.T2A (TAU_ITR192), SYN.F(ab′)2.HL.T2A (TAU_ITR191) and CAG.F(ab′)2.HL.T2A (TAU_ITR190).

When all data on delivery of viral genomes expressing antibody fragments are considered in aggregate, Fab.HL.T2A format appears to result in the highest expression of antibody fragment in target tissue.

Further, in comparing expression of anti-tau antibody fragments after IV delivery of VOY101 particles, brain levels were substantially higher than the level of expression seen after IV delivery of full length antibody.

In conclusion, these data showed that intravenous delivery of AAV particles (e.g., Voy101) encoding anti-tau antibodies or antibody fragments resulted in widespread vector genome biodistribution and therapeutically relevant antibody levels in mouse CNS tissues.

VII. Equivalents and Scope

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments in accordance with the disclosure described herein. The scope of the present disclosure is not intended to be limited to the above Description, but rather is as set forth in the appended claims.

In the claims, articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or the entire group members are present in, employed in, or otherwise relevant to a given product or process.

It is also noted that the term “comprising” is intended to be open and permits but does not require the inclusion of additional elements or steps. When the term “comprising” is used herein, the term “consisting of” is thus also encompassed and disclosed.

Where ranges are given, endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

In addition, it is to be understood that any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Since such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the compositions (e.g., any antibiotic, therapeutic or active ingredient; any method of production; any method of use; etc.) can be excluded from any one or more claims, for any reason, whether or not related to the existence of prior art.

It is to be understood that the words which have been used are words of description rather than limitation, and that changes may be made within the purview of the appended claims without departing from the true scope and spirit in its broader aspects.

While the present disclosure has been described at some length and with some particularity with respect to the several described embodiments, it is not intended that it should be limited to any such particulars or embodiments or any particular embodiment, but it is to be construed with reference to the appended claims so as to provide the broadest possible interpretation of such claims in view of the prior art and, therefore, to effectively encompass the intended scope. 

1. An AAV viral genome comprises: a. a 5′ inverted terminal repeat (ITR) sequence region; b. a promoter sequence region; c. at least one antibody polynucleotide, wherein said at least one antibody polynucleotide comprises a polynucleotide sequence with at least 90% identity, or encodes an amino acid sequence with at least 90% identity, to a sequence selected from the group consisting of SEQ ID NO: 1740-1989, 2241-2243, and 2169-2170; and d. a 3′ ITR sequence region.
 2. The AAV viral genome of claim 1 comprising: an exon sequence regions selected from the group consisting of SEQ ID NO: 2090-2094; an intron sequence region selected from the group consisting of SEQ ID NO: 2095-2105, 2240 and 2256-2258; a signal sequence region selected from the group consisting of SEQ ID NO: 1740, 1741, 1861, 2106-2117 and 2241; a tag sequence region selected from the group consisting of SEQ ID NO: 2118-2121 and 2255; and/or a filler sequence region selected from the group consisting of SEQ ID NO: 2125 and
 2126. 3-6. (canceled)
 7. The AAV viral genome of claim 1, comprising two antibody polynucleotides.
 8. The AAV viral genome of claim 7, wherein the two antibody polynucleotides are separated by a linker sequence selected from the group consisting of SEQ ID NO: 1724-1739, 2244-2254 and
 2259. 9. The AAV viral genome of claim 7 wherein a first antibody polynucleotide encodes an antibody heavy chain or a fragment thereof.
 10. The AAV viral genome of claim 7 wherein a second polynucleotide encodes an antibody light chain or a fragment thereof.
 11. The AAV viral genome of claim 1 comprising more than two antibody polynucleotides.
 12. The AAV viral genome of claim 8, encoding from 5′ to 3′; an antibody heavy chain, a linker sequence, and an antibody light chain; or an antibody light chain, a linker sequence, and an antibody heavy chain.
 13. (canceled)
 14. An AAV particle comprising the AAV viral genome of claim
 1. 15. The AAV particle of claim 14, wherein the sequence of the AAV viral genome is selected from the group consisting of SEQ ID NO: 1990-2075, 2137-2168, 2171-2237 and 2260-2321.
 16. The AAV particle of claim 14, comprising an AAV serotype selected from the group consisting of VOY101, VOY201, AAVPHP.B (PHP.B), AAVPHP.A (PHP.A), AAVG2B-26, AAVG2B-13, AAVTH1.1-32, AAVTH1.1-35, AAVPHP.B2 (PHP.B2), AAVPHP.B3 (PHP.B3), AAVPHP.N/PHP.B-DGT, AAVPHP.B-EST, AAVPHP.B-GGT, AAVPHP.B-ATP, AAVPHP.B-ATT-T, AAVPHP.B-DGT-T, AAVPHP.B-GGT-T, AAVPHP.B-SGS, AAVPHP.B-AQP, AAVPHP.B-QQP, AAVPHP.B-SNP(3), AAVPHP.B-SNP, AAVPHP.B-QGT, AAVPHP.B-NQT, AAVPHP.B-EGS, AAVPHP.B-SGN, AAVPHP.B-EGT, AAVPHP.B-DST, AAVPHP.B-DST, AAVPHP.B-STP, AAVPHP.B-PQP, AAVPHP.B-SQP, AAVPHP.B-QLP, AAVPHP.B-TMP, AAVPHP.B-TTP, AAVPHP.S/G2A12, AAVG2A15/G2A3 (G2A3), AAVG2B4 (G2B4), AAVG2B5 (G2B5), PHP.S, AAV1, AAV2, AAV2 variant, AAV2/3 variant, AAV2G9, AAV3, AAV3a, AAV3b, AAV3-3, AAV4, AAV4-4, AAV5, AAV6, AAV6.1, AAV6.2, AAV6.1.2, AAV7, AAV7.2, AAV8, AAV9, AAV9K449R, AAV9.11, AAV9.13, AAV9.16, AAV9.24, AAV9.45, AAV9.47, AAV9.61, AAV9.68, AAV9.84, AAV9.9, AAV10, AAV11, AAV12 and variants thereof.
 17. (canceled)
 18. The AAV particle of claim 16, where the amino acid sequence of VOY101 comprises SEQ ID NO:
 1. 19. The AAV particle of claim 14, comprising an AAV serotype of AAV2 or an AAV2 variant, AAV5 or an AAV5 variant, or AAV9 or an AAV9 variant. 20-23. (canceled)
 24. A pharmaceutical composition comprising the AAV particle of claim
 14. 25. A method of producing a functional antibody in a subject in need thereof, comprising administering to said subject the pharmaceutical composition of claim
 24. 26. The method of claim 25, wherein the level or amount of the functional antibody in the target cell or tissue after administration to the subject is from about 0.001 ug/mL to 100 mg/mL.
 27. The method of claim 25, wherein the functional antibody is encoded by the at least one antibody polynucleotide of the viral genome within said AAV particle.
 28. (canceled)
 29. A method for treating tauopathy in a subject in need, comprising administering to said subject a therapeutically effective amount of the pharmaceutical composition of claim
 24. 30. The method of claim 29 comprising administering the AAV particle by a delivery route selected from the group consisting of intravenous intraparenchymal, intracerebroventricular, and intracisternal. 31-36. (canceled)
 37. The methods of claim 29, wherein the tauopathy is selected from the group consisting of Alzheimer's disease (AD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Frontotemporal lobar degeneration (FTLD), Frontotemporal dementia, chronic traumatic encephalopathy (CTE), Progressive Supranuclear Palsy (PSP), Down's syndrome, Pick's disease, Corticobasal degeneration (CBD), Corticobasal syndrome, Amyotrophic lateral sclerosis (ALS), Prion diseases, Creutzfeldt-Jakob disease (CJD), Multiple system atrophy, Tangle-only dementia, and Progressive subcortical gliosis and other tau associated disease. 38-39. (canceled)
 40. The AAV genome of claim 1, further comprising a polyadenylation (polyA) signal sequence region, and wherein: the 5′ ITR sequence region is selected from the group consisting of SEQ ID NO: 2076 and 2077; the promoter sequence region is selected from the group consisting of SEQ ID NO: 2080-2089 and 2238-2239; the 3′ ITR sequence region is selected from the group consisting of SEQ ID NO: 2078 and 2079; and/or the polyA signal sequence region is selected from the group consisting of SEQ ID NO: 2122-212. 